2017 PHYS REV Grelina CCK glp1 Pyy Papeis Fisiológicos Na Obesidade Saúde PDF

Physiol Rev 97: 411– 463, 2017
Published December 21, 2016; doi:10.1152/physrev.00031.2014
GHRELIN, CCK, GLP-1, AND PYY(3–36):

SECRETORY CONTROLS AND PHYSIOLOGICAL
ROLES IN EATING AND GLYCEMIA IN HEALTH,
OBESITY, AND AFTER RYGB
Robert E. Steinert, Christine Feinle-Bisset, Lori Asarian, Michael Horowitz,
Christoph Beglinger, and Nori Geary
University of Adelaide Discipline of Medicine and National Health and Medical Research Council of Australia
Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide, Australia; DSM
Nutritional Products, R&D Human Nutrition and Health, Basel, Switzerland; Institute of Veterinary Physiology,
University of Zurich, Zurich, Switzerland; Department of Biomedicine and Division of Gastroenterology, University
Hospital Basel, Basel, Switzerland; and Department of Psychiatry, Weill Medical College of Cornell University,
New York, New York
Steinert RE, Feinle-Bisset C, Asarian L, Horowitz M, Beglinger C, Geary N.
L
Ghrelin, CCK, GLP-1, and PYY(3–36): Secretory Controls and Physiological Roles in
Eating and Glycemia in Health, Obesity, and After RYGB. Physiol Rev 97: 411– 463,
2017. Published December 21, 2016; doi:10.1152/physrev.00031.2014.—The
efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the man-
agement of obesity and type 2 diabetes mellitus and novel developments in gastrointestinal (GI)
endocrinology have renewed interest in the roles of GI hormones in the control of eating, meal-
related glycemia, and obesity. Here we review the nutrient-sensing mechanisms that control the
secretion of four of these hormones, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-
1), and peptide tyrosine tyrosine [PYY(3–36)], and their contributions to the controls of GI motor
function, food intake, and meal-related increases in glycemia in healthy-weight and obese persons,
as well as in RYGB patients. Their physiological roles as classical endocrine and as locally acting
signals are discussed. Gastric emptying, the detection of specific digestive products by small
intestinal enteroendocrine cells, and synergistic interactions among different GI loci all contribute
to the secretion of ghrelin, CCK, GLP-1, and PYY(3–36). While CCK has been fully established as
an endogenous endocrine control of eating in healthy-weight persons, the roles of all four hormones
in eating in obese persons and following RYGB are uncertain. Similarly, only GLP-1 clearly contrib-
utes to the endocrine control of meal-related glycemia. It is likely that local signaling is involved in
these hormones’ actions, but methods to determine the physiological status of local signaling
effects are lacking. Further research and fresh approaches are required to better understand
ghrelin, CCK, GLP-1, and PYY(3–36) physiology; their roles in obesity and bariatric surgery; and
their therapeutic potentials.
I. INTRODUCTION 411 century. These discoveries provided a novel signaling mech-

II. GI MOTOR FUNCTION 415 anism for the control of gastrointestinal (GI) physiology,
III. GHRELIN 420 which supplanted Pavlov’s “nervism” doctrine (44, 401,
IV. CHOLECYSTOKININ 425 566a). From this beginning, endocrinology rapidly grew
V. GLUCAGON-LIKE PEPTIDE-1 429 into a discipline crucial to virtually all of physiology and
VI. PYY(3–36) 435 medicine.
VII. DISCUSSION 440
The contributions of GI hormones to insulin secretion and
glycemic regulation were identified in the 1960s (109, 782).
I. INTRODUCTION
The discovery of CCK’s satiating effect in the 1970s (278)
ushered GI hormones into the physiology of eating. By the
A. Background 2000s, at least a dozen GI hormones had been hypothesized
to contribute to eating (836). GI hormones secreted in re-
The first hormones, secretin (66), gastrin (229), and chole- sponse to eating, however, were mainly considered to be
cystokinin (CCK) (362), were discovered in the early 20th phasic signals sculpting the timing and size of individual
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STEINERT ET AL.
meals and were not thought to be relevant for the tonic ingly important issue in GI endocrinology, whether the hor-
control of total energy intake and body-weight regulation mones’ mode of signaling in these situations is classically
(e.g., Refs. 172, 521, 672, 837). This view soon changed. In endocrine or local; 4) given the close relationship of GI
2002, Cummings et al. (174) reported that levels of the endocrine and GI motor physiology, the role of GI motility
gastric hormone ghrelin, which had been shown to increase in the hormones’ effects; 5) whether obesity [i.e., body mass
eating when infused intravenously in humans (839), were index (BMI); weight in kg/(height in m)2 ⱖ30 kg/m2], alters
inversely related to body adiposity in healthy-weight, obese, the hormones’ effects on eating or glycemic control, and 6)
and weight-reduced humans, consistent with a tonic signal- because of the marked alterations in nutrient delivery into
ing function. Recent clinical trials indicate that treatment the small intestines and contact with enteroendocrine cells
with long-acting glucagon-like peptide-1 (GLP-1) receptor after RYGB (FIGURE 1), the hormones’ contributions to the
agonists such as liraglutide [Victoza for type 2 diabetes effects of RYGB on eating and glycemic control.
mellitus (T2DM) and Saxenda for weight control, Novo
Nordisk, Bagsvaerd, Denmark] leads to weight loss and
amelioration of T2DM (335, 414, 581). Finally, changes in B. Approach
GI hormone secretion provide plausible mechanisms for the
remarkable therapeutic efficacy of bariatric surgery, espe- 1. Why focus on meals?
cially Roux-en-Y gastric bypass (RYGB), to reduce adipos-
ity and improve glycemic control (113, 310, 421, 513, 551, Total amount eaten and glycemic control are critically de-
712). pendent on the control of and physiological responses to
individual meals, and a significant component of these func-
In light of this, we review, 1) the secretion of ghrelin, CCK, tions is thought to be mediated by ghrelin, CCK, GLP-1,
GLP-1, and peptide tyrosine tyrosine [PYY(3–36)] around and PYY(3–36) secretion, as schematized in FIGURE 2.
meals; 2) the contributions of these hormones to the control
of meal size, meal timing, and meal-related glycemia, but as The timing, size, and content of meals provide a complete
explained below, not to hedonics; 3) because it is an increas- description of what, when, and how much (in terms of g,
A B
Ghrelin CCK GLP-1 PYY Intact GI tract GI tract after RYGB
Stomach
Small intestine
Colon
FIGURE 1. Schematic depictions of the localization of enteroendocrine cells and changes after RYGB.
A: distribution of enteroendocrine cells secreting ghrelin, CCK, GLP-1, and PYY in the stomach (pink),
duodenum (yellow), jejunum (green), and ileum (violet). Black areas indicate the relative densities of expression
of enteroendocrine cells producing the hormones indicated. Enteroendocrine cells secreting particular hor-
mones were initially categorized histologically, e.g., I cells for CCK, L cells for enteroglucagons and PYY, etc.
(166, 567, 591). It is now clear, however, that this categorization is not a reliable guide to hormone secretion.
Rather, individual enteroendocrine cells secrete variable mixtures of hormones (231, 303, 597, 738).
Bottom salmon rectangle, proximal large intestine. B: intact gastrointestinal tract (left) and gastrointestinal
rearrangement after RYGB (right). Pink areas are stomach, salmon areas are large intestine (⬃1.5 m long in
healthy adults), yellow is duodenum (typically ⬃25 cm long), green is jejunum (⬃2–3 m), and violet is ileum
(⬃3– 4 m). For RYGB, the stomach is divided into a small upper pouch with a volume of ⬃25 ml and an isolated
gastric remnant, the small intestine is divided ⬃50 cm from the pylorus, and the distal limb of the small
intestine (Roux or alimentary limb) is brought up to the gastric pouch and connected to it by an end-to-side
gastroenterostomy. As a result, ingested food enters the small gastric pouch and empties directly into the
jejunum. The gastric remnant and isolated ⬃50 cm of small intestine (“biliopancreatic limb”) is connected
to the jejunum ⬃150 cm distal to the gastroenterostomy. The small intestine distal to the anastomosis is
called the common channel.
412 Physiol Rev • VOL 97 • JANUARY 2017 • www.prv.org

PRANDIAL PHYSIOLOGY OF GHRELIN, CCK, GLP-1, AND PYY(3–36)
kcal, or macronutrients) is eaten. Meal patterns are pro- shift from nutritional homeostasis to behavioral neurosci-
duced by species-specific physiological controls as well as ence.”
environmental, social, and cultural contingencies. The con-
trol of meal size is disturbed in psychiatric eating disorders Ghrelin, CCK, GLP-1, and PYY(3–36) contribute to three
(271, 483, 743). In addition, obese individuals eat larger of the putative motivational processes that provide the basic
meals than healthy-weight individuals (5, 74, 189, 497) unconditioned control of meal initiation and meal size (85,
(healthy body weight is BMI ⱖ18.5 and ⬍25 kg/m2). Thus 86, 271): 1) hunger, which refers to the process energizing
the physiology of individual meals is crucial for understand- the acquisition of food and meal initiation; 2) satiation,
ing normal and disordered eating, including the chronic which leads to ending the meal; and 3) postprandial satiety,
overeating that has led to the obesity epidemic (368, 741, which inhibits eating after meals and prolongs the intermeal
792). Smith (702) referred to the recognition of the central interval. The hormones’ possible roles in a fourth meal-
role of meals in the physiology of eating as “a paradigm control process, flavor hedonics, and the central neural
mechanisms integrating their effects are not reviewed, as
these topics have been adequately reviewed elsewhere (for
reviews of the hormones’ hedonic effects, see Refs. 24, 212,
467, 499, 571, 699, 700, 827; for reviews of their central
processing, see Refs. 75, 76, 291, 524, 623, 625).
It has long been known that meal-stimulated insulin release

accounts for about half of total daily insulin secretion (408,
Inhibition
of eating
592, 593). More recently, measurement of glycated hemo-
globin A1c (HbA1c) in T2DM patients with well-controlled
glucose levels (HbA1c ⬍7.3%), i.e., patients most closely
Gastric emptying resembling metabolically healthy persons, revealed that
Digestion to MS, FFA, AA, etc.
Small-intestinal nutrient sensing meal-related increases in blood glucose account for ⬃70%
of the total increment in diurnal blood glucose levels over
fasting levels (509, 621). (“Meal related” indicates both
during and after meals and is clearer than “prandial,”
which sometimes is used to indicate only during meals.)
Ghrelin
Two of the principal factors related to meal-related in-
CCK creases in blood glucose are GI functions: 1) gastric empty-
ing, which determines the rate of appearance of glucose in
GLP-1
the small intestines, and, ordinarily, in the blood, and 2) the
PYY(3-36) release of incretin hormones, i.e., GI hormones that stimu-
late insulin secretion (472). Thus, because CCK and
Secretion
PYY(3–36) contribute to gastric emptying, because GLP-1
is one of the principal incretin hormones (together with
glucose-dependent insulinotropic peptide, GIP), and be-
cause ghrelin, CCK, GLP-1, and PYY(3–36) may have other
effects that influence meal-related glycemia, meal physiol-
ogy is an integral component of glycemic control.
Reduced
meal-related 2. Why a “physiological” approach?
hyperglycemia
Since its beginning, endocrinology has been organized
FIGURE 2. Overview of the hypothesized physiological roles of ghre- around specific empirical criteria to identify hormones and
lin, CCK, GLP-1, and PYY(3–36) in the control of eating and of meal- their normal physiological functions (59, 156, 293, 489,
related glycemia. Gastric emptying, which controls the rate of appear- 833). The first criteria were stated implicitly by Bayliss and
ance of ingested food in the small intestine, intestinal transit, rate of
Starling in 1902 (66) in their description of the discovery of
digestion, and small intestinal nutrient sensing are the major deter-
minants of the inhibition of ghrelin secretion and the stimulation of secretin (TABLE 1). In their “crucial experiment,” they ob-
CCK, GLP-1, and PYY(3–36) secretion during and after meals. Left: served that pancreatic secretion was stimulated both by acid
changes in hormone levels lead to GI and central nervous system introduced into a denervated loop of an anesthetized dog’s
events whose outcome is to inhibit eating. Right: changes in hor- jejunum and by intravenous injection of an extract of jeju-
mone levels lead GI, pancreatic, hepatic, and central nervous sys-
nal mucosa. This effectively began a new chapter in physi-
tem events whose outcome is to dampen postprandial increases in
blood glucose. All four hormones have been hypothesized to contrib- ology. Starling coined the term hormone, from the Greek
ute to each type of outcome. MS, monosaccharides; FFA, free fatty for I arouse or excite, in 1905 (711) based on the secretin
acids; AA, amino acids. work, on earlier studies of the pressor effect of adrenal
Physiol Rev • VOL 97 • JANUARY 2017 • www.prv.org 413

STEINERT ET AL.
pre- and postsynaptic proteins, and rabies virus moves ret-

Table 1. Evolution of endocrine criteria rogradely through them. This neuropod mode of action
A. William Bayliss and Ernest H. Starling (1902)
presumably mediates more specific cell-to-cell signaling
1. The adequate stimulus produces the response after than paracrine mechanisms. One possibility is that this sig-
complete denervation of the hormone-producing tissue. naling contributes to enteric nervous system reflexes linking
2. Intravenous injection of an extract of the hormone- the proximal and distal small intestine, which, as described
producing tissue produces the response. below, appear important in the control of GI hormone se-
B. Edward A. Doisy (1936) cretion. FIGURE 3 summarizes the signaling modes of GI
1. Identification of the tissue that produces a hormone. hormones.
2. Development of bioassay methods to identify the
hormone.
The criteria used here for normal, endogenous physiologi-
3. Preparation of active extracts that can be purified,
using the relevant bioassay. cal function are listed in TABLE 2. Criteria 1 and 2 address
4. Isolation, identification of structure, and synthesis of the plausibility that the candidate signal controls a particu-
the hormone. lar function, criteria 3–5 concern the candidate signal’s suf-
C. Morton I. Grossman (1973) ficiency, and criterion 6 concerns its necessity. For hor-
1. The adequate stimulus produces a response in a mones acting via an endocrine mode, endocrine tests of
distant target.
criterion 1 may be based on concentrations of the molecule
2. The response persists after cutting all nerves
connecting the site of stimulation and the target.
in the blood and at its site of action, and criteria 3, 4, and 6
3. The response is produced by an extract of the may be tested with intravenous infusions (unless blood-
hormone-producing tissue. borne agonists or antagonists do not readily access the re-
4. The effect is produced by infusing exogenous hormone ceptors, for example because of the blood-brain barrier).
in amounts and molecular forms that copy the increase in Plasma levels and intravenous infusions, however, do not
blood concentrations produced by the adequate stimulus for
endogenous release. provide adequate tests of paracrine or neuropod signaling.
This is because intravenous infusion of a hormone, even if it
See text for references and discussion.
matches the hormone’s meal-related changes in the blood,
may not mimic its concentration at paracrine or neuro-
pod sites of action, i.e., in the lamina propria or at the site
epinephrine by Oliver and Schäfer (556), and on his belief in
of close appositions with other cells, respectively. The
the importance of chemical control in physiology (320). In
same goes for agonist or antagonist administration.
the subsequent decades, isolating hormones from gland tis-
Thus, for paracrine or neuropod modes of action, the
sue was a major enterprise and was organized around ad-
ditional criteria, such as Doisy’s (218, 833) (TABLE 1). The criteria remain theoretical possibilities, at least in hu-
development of radioimmunoassay and other accurate as- mans, because, at present, there are no validated means
say methods beginning in the mid-20th century brought to deliver hormones locally into the lamina propria or the
additional criteria, based on appropriate changes in plasma close appositions formed by neuropods, or to measure
hormone levels, such as Grossman’s (293) (TABLE 1). Ra- their concentrations at such sites. In animals, however,
dioactive (and other) molecular-labeling methods also en- these limitations soon may be surmounted, for example,
abled the study of hormone receptors, and criteria based on by targeting the lamina propria with infusions into intes-
receptor function were added (267, 270, 703), as discussed tinal lumen (147).
further below.
A related issue is that multiple parameters of hormone se-
It is now clear that many hormones signal locally as well as cretion other than plasma concentrations may encode feed-
via the classic blood-borne, endocrine mode (163, 463, back signals controlling eating. These include times of onset
611). Local signaling in the GI tract can take three forms. of changes in plasma levels, rates of change, pulsatility,
First, hormones may act in a paracrine mode, i.e., be re- and effects of sustained or integrated levels versus mo-
leased as usual into the GI lamina propria and act on neigh- mentary levels. Unfortunately, the parameters that actu-
boring nonneural cells before absorption. Second, they may ally serve as endogenous physiological signals have not
act in a neuroendocrine-like mode if they affect neural af- been intensively studied. Rather, researchers have mod-
ferents in the laminal propria. Third, they may act in a eled mainly a single parameter, the peak plasma level,
neurocrine-like mode following release from axonlike cyto- and peaks have been modeled only crudely by continuous
plasmic extensions of the enteroendocrine cells, called neu- infusions that do not consider the duration or timing of
ropods (90, 418). CCK- and PYY-containing neuropods, the peaks. Therefore, for the purposes of evaluating cri-
ending mainly in close apposition to glial cells of the enteric terion 1, “physiological” endocrine doses are provision-
nervous system, were recently described in mice (92, 93). ally defined as those reproducing the peak plasma levels
Neuropods appear to have a synapse-like function because produced by mixed-nutrient meals (TABLE 3). As limited
there are accumulations of secretory vesicles near the appo- as this definition is, it is at present the state of the art and
sitions, the neuropods and target cells express characteristic has proven quite useful.

The ability to analyze hormone function with agonists and onto gastric emptying. Therefore, the review begins with an
antagonists (criterion 6) is linked to developments in recep- introduction to the effects of GI motor function on eating
tor pharmacology and receptor-subtype analyses. The use and glycemia in health, obesity, and after RYGB.
of antagonists in particular is now considered one of the
cardinal criteria for physiological function. These tools also
II. GI MOTOR FUNCTION
demand careful interpretation if the biological half-life, re-
ceptor affinity, relative access to receptors beyond the
blood-brain barrier, etc., differ between the hormone and A. Gastric Accommodation and Emptying
the agonist or antagonist. For example, the eating-inhibi-
tory effects of the long-lasting GLP-1 agonist exendin-4 Physical digestion of solid food begins in the mouth, but is
differ markedly from those of native GLP-1. primarily a gastric function (126, 127, 318, 341, 366, 481,
578, 724). Gastric volume during the meal usually exceeds
3. Why consider GI motor function? the volume of ingesta due to gastric secretions and swal-
lowed saliva and air (118, 282). Vago-vagal gastric-accom-
GI endocrine function and GI motor function are so closely modation reflexes increase gastric volume as meals prog-
related that one cannot be understood without the other. ress, avoiding significant increases in intragastric pressure
Gastric emptying and intestinal transit determine which en- or gastric-wall tension (43, 405). The lack of stimulation of
teroendocrine cells are exposed to chyme and for how long. gastric-tension receptors ensures that accommodation does
This in turn affects GI hormone secretion, which feeds back not lead to aversive sensations, although they do appear
sufficient to elicit a pleasant sensation of fullness (215, 464).
Accommodation reflexes are triggered mainly by gastric
IE LMM
mechanoreceptors and intestinal nutrient receptors and are
mediated in part by CCK (43, 246).
Lumen Lamina
propria
FIGURE 3. Schematic of the small intestinal mucosa showing po-
tential modes of action of CCK, GLP-1, and PYY. The mucosa in-
cludes the epithelial cell layer (IE) on the luminal side, the lamina
propria, and the lamina muscularis mucosae (LMM), which limns
the submucosa and underlying serosa (not shown). The epithelium
consists of enterocytes (tan), which are specialized for nutrient
1 Endocrine absorption, enteroendocrine cells (blue, villi not shown), which se-
Digested crete GI hormones, and other cell types (not shown). Digested nu-
nutrients trients activate specific nutrient receptors and transporters (orange
⬍) expressed on the apical surface of enteroendocrine cells, leading
to secretion of CCK, GLP-1, and PYY from the basolateral side of
2 Neurocrine enteroendocrine cells. Four modes of action are diagrammed. Mode
1 is the classical endocrine mode, in which hormones diffuse from
the lamina propria into mesenteric capillaries (salmon), which drain
into the hepatic-portal vein and finally the systemic circulation, allow-
ing hormones to act on distant targets. Modes 2– 4 show variations
3 Paracrine of local actions. Mode 2 is a neuroendocrine mode, in which hor-
mones in the lamina propria activate vagal afferents (green arrow),
which in turn stimulate brain-mediated responses. Mode 3 is the
paracrine mode, in which hormones in the lamina propria act on
receptors (black ⬍) on nearby cells, either neuroendocrine cells or
other cell types. Mode 4 shows the anatomical basis for a neuropod
mode of action, which has been described for enteroendocrine CCK
4 Neuropod and PYY cells, and may exist for other GI hormones. This involves
hormone release from enteroendocrine-cell neuropods that end in
synapse-like appositions to glial cells of the enteric nervous system
and other cell types. Note that the hormone concentrations involved
Afferent in these different modes vary: hormone concentrations in the small
gap between neuropods and adjacent cells are likely to be highest,
paracrine and vagal neuroendocrine signaling may be the next high-
est hormone concentrations, endocrine signaling in the liver involves
moderate hormone concentrations, and endocrine signaling in
which hormones reach their receptors via the systemic circulation
involves relatively low hormone concentrations. Hormones also en-
ter the lymph from the lamina propria via bulk flow (not shown), but
Efferent this is not known to be functionally relevant. Although ghrelin secre-
tion is not stimulated directly by nutrients, secreted ghrelin may act
in the modes shown here.

STEINERT ET AL.
duce semi-solid chyme. When chyme particles reach a size

Table 2. Criteria to assess physiological status of GI of ⬃1–2 mm, they are emptied through the pylorus into the
hormones in meal-related functions duodenum, a process that involves coordinated antropylo-
1. Concentrations of the hormone change at the site of ric propulsive pressure waves, pyloric-sphincter relaxation,
action in a pattern consistent with the effect.* and duodenal pressure waves. The delay until the first emp-
2. Cognate receptors for the hormone are expressed at its tying of solid food, known as the lag phase, can last from a
site(s) of action. few minutes to over an hour, depending on the physical
3. Exogenous administration of the hormone in amounts
duplicating the meal-related changes in endogenous
characteristics of the food. Once in the proximal small in-
patterns at the site of action produces the effect. testine, chyme initiates several neural and GI-hormonal re-
4. Administration of secretagogues for the hormone flexes that decelerate emptying.
produce effects similar to the effect of the hormone.
5. The hormone’s effect occurs in the absence of abnormal When gastric emptying is measured for intervals approxi-
behavioral, physiological, or subjective effects.
mating the normal intermeal interval, beginning after the
6. Administration of selective agonists and antagonists of
the hormone’s receptors produce effects that are lag phase for solids and ignoring pulsatile pyloric chyme
consistent with their receptor pharmacologies.†‡ propulsion, exponential curves provide good fits (FIGURE 4)
(118, 123, 126, 129, 158, 314, 349, 481, 663, 693, 744,
*These criteria extend earlier versions (265, 268, 696) to accom-
modate paracrine and neuropod signaling as well as endocrine sig- 795, 855). The Weibull or “power-exponential” function
naling, as described in the text. †At a minimum, the change in fits the lag phase as well (118, 126, 234, 347, 372, 452, 645,
concentrations of the proposed signal should precede the effect;
see Geary (265) for discussion. For example, administration of spe-
772).
cific and potent receptor antagonists should delay or reduce eating
in the case of a hunger signal or increase eating in the case of a Emptying patterns are affected by meal volume, osmotic
satiation signal. ‡We do not include phenotypic evaluation of global
transgenic or spontaneous genetic loss-of-function models in this
pressure, energy density, digestibility, and macronutrient
criterion. These are valuable research tools, but complications due adaptation (97, 162, 175, 176, 340). When meals contain
to developmental compensatory effects, pleiotropic actions, and both liquids and solids, the two phases empty differentially,
species differences preclude their use as a “necessity” criterion for
physiological function. Rapidly inducible, tissue-specific reductions in although each affects the other, with liquids generally emp-
gene function, however, may complement the use of receptor an- tying faster (345, 481, 643). Gastric emptying is somewhat
tagonists in establishing necessity. slower in women than men (73, 187, 200, 295, 350, 394),
although whether it is affected by the menstrual-cycle phase
is not clear (101, 200). Normal aging apparently has little
Ingested liquids are distributed evenly throughout the stom-
ach and begin emptying almost immediately. In contrast, effect (606). As a result of these factors, there is consider-
ingested solids are initially restricted mainly to the fundus able interindividual variability in gastric emptying rate. In
and move gradually to the antrum, where they are mixed
with gastric secretions and reduced in size by antral tritura-
tion, i.e., by churning and grinding movements that pro- Meal 1 IMI Meal 2
100 0
Table 3. Physiological endocrine doses of ghrelin, CCK, GLP-1,
and PYY(3–36) in healthy-weight humans 80 20
Solid
food
% Remaining
% Emptied
Physiological Dose,
Hormone pmol·kgⴚ1·minⴚ1 Reference Nos. 60 40
Ghrelin ? (⬍0.3)* 441, 759 40 60

CCK 0.2–0.7 54, 297, 433, 435 Liquid
20 food 80
GLP-1 0.3–0.90† 69, 253, 299, 659
PYY(3–36) ? (⬍0.2)‡ 10, 192, 196, 421
0 100
Physiological endocrine doses (pmol·kg⫺1·min⫺1) are those re-
0 1 2 3 4 5
ported to reproduce the peak plasma levels produced by mixed-
nutrient meals [CCK, GLP-1, PYY(3–36) or premeal levels (ghrelin)]. Hours
*In one study, infusion of 0.3 pmol·kg⫺1·min⫺1 acyl ghrelin increased FIGURE 4. Typical patterns of gastric emptying of solid (green) and
plasma total ghrelin levels 2.2-fold to about the fasting level (759); in liquid (red) foods in relation to meals and intermeal intervals. De-
another study, infusion of the same dose after breakfast increased pending on the physical digestibility of solid foods, emptying during
acyl ghrelin 2.4-fold above the fasting level (441); the effects of the first several minutes is very slow (the lag phase), whereas it is
lower doses have not been reported. †Physiological GLP-1 doses are
uncontrolled and rapid for liquids. The overall shapes of the gastric
based on across-study comparisons. ‡Physiological PYY(3–36)
doses are based on one study of meals and infusions (196) and emptying curves for solid food after the lag phase and for liquid foods
separately reported meal and infusion effects (10, 192, 421); ef- are exponential, although significant extents of each approximate
fects of doses ⬍0.2 pmol·kg⫺1·min⫺1 on eating have not been linear functions. As described in the text, gastric emptying plays
reported. important roles in the control of eating and meal-related glycemia.

contrast, intraindividual variability is low under laboratory tying elicited by intragastric lipid infusion (374), but
conditions (532). whether reproducing endogenous amounts and patterns of
ghrelin is sufficient to stimulate gastric emptying and
Neural and endocrine reflexes are generally thought to syn- whether ghrelin antagonists inhibit gastric emptying have
ergize in the control of gastric emptying (126, 216, 555). not been tested in humans. Thus ghrelin does not yet fulfill
The importance of the vagal contribution is underscored by criteria 3 and 6 (TABLE 2) for having an endocrine role in
the decrease in emptying of solid foods after vagotomy gastric emptying. Similarly, a supraphysiological ghrelin in-
(405). The roles of ghrelin, CCK, GLP-1, and PYY(3–36) fusion elicited phase III MMC activity, but smaller doses
are reviewed in section IIC. did not (203, 748), and endogenous phase III MMC activity
was not temporally associated with plasma ghrelin concen-
trations (although phase III MMC activity was associated
B. Small Intestinal Motility with motilin levels) (204). Thus these tests did not produce
evidence that ghrelin fulfills criteria 1 or 3 (TABLE 2) for an
The contributions of segmentation, mixing, and propulsion endocrine effect on GI motility.
of chyme in the small intestine to intestinal nutrient sensing
and the control of eating and glycemia are not well under- Several studies indicate that CCK meets both criteria 1 and
stood. Challenges include: 1) present methods to measure 6 (TABLE 2) for having an endocrine role in gastric emptying
segmentation, mixing, and propulsion of chyme are limited, of liquid food (262, 263, 436, 447, 495, 674; but see Ref.
although novel approaches may soon accelerate progress 433 for a negative report). Animal studies indicate that
(30, 33, 87, 220); and 2) the simultaneous changes in gastric CCK slows gastric emptying via vago-vagal reflexes stimu-
accommodation, gastric emptying, and GI-hormone secre-
lated by both endocrine and paracrine signaling (216, 555,
tion are difficult to control (641, 681, 682, 718). Multivar-
823). CCK also fulfilled criteria 1, 4, and 6 for endocrine
iate statistics, such as the approaches of Seimon et al. (683)
roles in the increases in tonic and phasic pyloric pressures
and Acosta et al. (5), provide a useful strategy to dissect
and reductions in antral and duodenal pressures stimulated
these diverse factors functionally.
by intraduodenal lipids (102, 190, 259, 316, 584), re-
sponses that presumably contribute to CCK’s inhibitory
Two pharmacological studies suggest an important role for
effect on gastric emptying (382). One study in humans
small intestinal motility in incretin hormone secretion. In
failed to detect an effect of CCK-receptor antagonism on
both, healthy-weight subjects received intraduodenal infu-
small intestinal transit time (495).
sions of glucose, and intraduodenal pressure and flow
events were assessed by manometry and impedance mea-
surements. Pretreatment with hyoscine butylbromide (137) There is also support for GLP-1 as an endocrine control of
increased intraduodenal waves for 10 min and reduced flow gastric emptying. Physiological doses of GLP-1 slowed
events for 60 min. This was associated with decreased emptying of liquid meals (541, 822), supporting criterion 3
(TABLE 2), and administration of the GLP-1 receptor antag-
plasma level GIP at 10 and 20 min, suggesting that normal
GIP release depends on the spread of glucose through duo- onist exendin(9 –39) accelerated gastric emptying in two
denum and proximal jejunum. In contrast, pretreatment studies (41, 196), supporting criterion 6. Exendin(9 –39)
with metoclopramide (411) stimulated duodenal pressure failed to affect gastric emptying in three other studies (531,
waves, but did not affect flow events. Metoclopramide pro- 546, 650), however, suggesting that differences in test meal
duced marked increases in plasma GLP-1 and GIP, suggest- characteristics, plasma glucose levels, or other situational
ing that increased mixing of the luminal contents increased variable may contribute to GLP-1’s influence on gastric
their contact with enteroendocrine cells, thus increasing in- emptying. Exendin(9 –39) also stimulates PYY(3–36) secre-
cretin secretion. By extension, small intestinal motility may tion, which may slow gastric emptying and contribute to
also affect ghrelin, CCK, and PYY secretion. these variable results (41, 230, 665, 670, 721, 843). Intra-
venous infusion of physiological doses of GLP-1 also stim-
When the stomach is empty, small intestinal peristaltic ac- ulated tonic and phasic pyloric pressures and reduced antral
tivity is controlled by phase III activity of the migrating and duodenal pressure waves (662), and infusion of exen-
motor complex (MMC), which originates in the stomach in din(9 –39) abolished glucose-induced changes in antropylo-
humans, rats, and mice (203, 266, 748, 853) and appears to roduodenal pressures (664), indicating a role for GLP-1 in
be stimulated by motilin (203). small intestinal motility.
Supraphysiological PYY(3–36) infusions slowed gastric

C. Roles of Ghrelin, CCK, GLP-1, and emptying in two studies (26, 834). Savage et al. (659) re-
PYY(3–36) ported that emptying of a non-nutrient liquid meal was
slowed by infusion of 0.4 pmol·kg⫺1·min⫺1 PYY(3–36).
Supraphysiological doses of ghrelin accelerated gastric They measured only 0.18 pmol·kg⫺1·min⫺1 PYY(3–36) at
emptying (429) and reversed the inhibition of gastric emp- the tip of the catheter, however, PYY(3–36) may meet the

STEINERT ET AL.
physiological-dose criterion (criterion 2, TABLE 2) for hav- A Meal 1 IMI Meal 2

ing a physiological endocrine role in gastric emptying. Stud-
ies with PYY(3–36) antagonists have not yet been reported.
PYY(3–36) has been hypothesized to mediate the “ileal
brake” on gastric emptying, a term referring to the ability of
nutrients in the ileum to slow gastric emptying. In support
of this, intra-ileal infusions of triglycerides, free fatty acids,
sucrose, or casein increased plasma PYY(3–36) levels and
slowed gastric emptying in several studies (585, 708, 709,
Gastric emptying high Gastric emptying low
787). Whether endocrine, paracrine, or neuropod PYY(3– Gastric volume high Gastric volume low
36) signaling mediates this effect is not known. Whether
PYY(3–36) affects small intestinal motility has not been
studied in humans. Intravenous infusion of PYY(3–36) and
B
ileal infusion of a mixed-nutrient solution similarly in-
creased the cycle length of phase III MMC in dogs (819),
but the relevance of this for humans is uncertain because the
control of the phase III MMC differs in dogs and humans – + CCK
GLP-1
(554). Gastric Ghrelin PYY(3-36)
emptying
– +
In summary, different degrees of evidence support the phys-
iological roles for ghrelin, CCK, GLP-1, and PYY(3–36) in
GI motility. An important feature of these relationships is
that gastric volume, gastric emptying, intestinal-nutrient Small-intestinal
nutrient sensing
sensing, and the secretion of these four hormones are linked
in negative-feedback loops (FIGURE 5).
FIGURE 5. Gastric volume, gastric emptying, and ghrelin, CCK,

D. Eating GLP-1, and PYY(3–36) secretion in relation to meals. A: eating a
meal increases gastric volume-related mechanoreception (bold
green arrows), which increases satiation signaling via neural affer-
Perhaps the oldest mechanistic explanation for eating is ents, and increases gastric emptying and the delivery of ingested
Galen’s suggestion that hunger results from gastric “pangs nutrients into the small intestine (bold red arrow), which increases
and gnawing sensations” (7, 482). These sensations may satiation and satiety signaling and decreases hunger signaling. As
result from phase III MMC. 1) In 12 h-fasted subjects, sub- the intermeal interval (IMI) progresses, volume sensing and gastric
emptying progressively decrease (thin red and green arrows).
jective hunger ratings were closely associated with the in- B: gastric emptying determines the rate of appearance of nutrients
tensity of gastric motility during both spontaneous phase III into the small intestine and, together with the rate of digestion and
MMC and phase III MMC elicited by erythromycin, a mo- small-intestinal motility, controls small intestinal-nutrient sensing. For
tilin agonist. 2) Erythromycin infusion elicited meal re- most meals, small intestinal-nutrient sensing inhibits ghrelin secretion
quests (205, 746). When spontaneous eating was measured (red arrow, ⫺) and stimulates CCK, GLP-1, and PYY secretion (green
arrows, ⫹). In turn, ghrelin stimulates (green arrow, ⫹) and CCK,
in another study, however, no premeal increases in gastric GLP-1, and PYY(3–36) inhibit (red arrows, ⫺) gastric emptying.
motility occurred (728). In addition, under other condi- Note that each feedback loop is negative, as indicated by the change
tions, erythromycin decreased rather than increased food in sign (e.g., red to green) between (small intestinal-nutrient
intake (770). Furthermore, phase III MMC develop only sensing)–(hormone secretion) and (hormone secretion)–(gastric
when the stomach is nearly empty, which usually occurs emptying).
only after overnight fasts, yet subjective hunger is usually
quite low in the morning (660) and breakfast is typically the
smallest meal of the day. Thus the role of gastric motility in size (273). 4) Pharmacological inhibition of the gastric-ac-
hunger remains doubtful. commodation reflex decreased gastric volume during a
meal and decreased meal size (747). 5) Rapid intragastric
Several lines of evidence support the hypothesis that in- glucose infusions increased fullness more than intraduode-
creased gastric volume contributes to satiation. 1) Ratings nal infusions roughly matched to the rate of gastric empty-
of fullness were correlated with total gastric volume and ing (719), although it was not clear whether this was due to
with antral cross-sectional area after both liquid and solid gastric-volume detection because the intragastric infusions
test meals (201, 282, 351, 373, 474, 655, 730, 794). 2) also increased GLP-1 and PYY(3–36) secretion more than
Manipulations designed to selectively increase gastric vol- the intraduodenal infusions. Interestingly, gastric-volume
ume increased fullness ratings and decreased eating (331, effects appear to synergize with postgastric satiation signals
475, 630 – 632). 3) Inflation of an intragastric balloon dur- because oral nutrient preloads together with intraduodenal
ing meals also increased fullness ratings and decreased meal nutrient infusions (133, 480, 552), CCK infusions (528), or

GLP-1 infusions (199) each decreased eating more than the 497) in obese relative to healthy-weight people. These in-
individual manipulations. consistent results may be related to several differences
among the studies, including differences in the nutrient
Gastric-volume signals are thought to control eating via composition of the test meals and methodological differ-
mechanoreceptors that are tuned to both tension and ences (e.g., scintigraphy vs. less direct measures). In con-
stretch or length (294, 366, 560, 579) and are linked to the trast, a large scintigraphic study (389 subjects) demon-
CNS by vagal and spinal visceral (splanchnic) afferents strated clearly that overweight and obesity are associated
(272, 791, 809). In rats, these include polymodal vagal with increased gastric emptying rates of both solid and liq-
afferents whose response can be increased severalfold by uid foods (5). Interestingly, the degrees of increase were
combinations of gastric fill and CCK infusion (671) or in- similar in overweight, obese, and morbidly obese (i.e., BMI
fluenced oppositely by CCK and ghrelin treatment (217). ⱖ35 kg/m2) subjects (decreases of ⬃20% in solid-meal half-
Thus neural information processing controlling GI function emptying time and ⬃30% in liquid-meal half-emptying
and eating appears to begin at the level of the vagal affer- time in each group). This suggests increased gastric-empty-
ents. ing rate is more likely to be a permissive rather than an
effective cause of obesity.
As mentioned above, negative-feedback loops link gastric
volume and gastric emptying to intestinal nutrient sensing Manipulations of gastric volume may contribute to obesity
and to ghrelin, CCK, GLP-1, and PYY(3–36) secretion (FIG- therapy. Consistent with this possibility, some data relate
URE 5). The relationship of these feedback loops to satiation is the eating-inhibitory, weight-reducing, and glycemic effects
complex because both gastric and postgastric signals contrib- of the GLP-1 receptor agonist liraglutide to reduced gastric
ute to satiation. Thus, depending on the circumstances, accel- emptying (343, 789). Furthermore, implantable devices de-
erating gastric emptying may either decrease satiation by designed to electrically stimulate the vagus in a way that
creasing gastric-volume signals or increase satiation by in- blocks vagal signaling reduced subjective hunger, increased
creasing postgastric signals. This point is underscored by fullness, decreased body weight, and improved glycemic
the report (770) that erythromycin accelerated gastric emp- regulation in clinical trials (89, 134, 353, 654, 656, 689).
tying and decreased rather than increased meal size in a The most compelling of these was a randomized, double-
group of overweight (i.e., BMI ⱖ25 and ⬍30 m/kg2) and blind, sham-controlled trial involving 239 obese patients
obese (BMI ⱖ30 kg/m2) subjects. Finally, recent data sug- (353). Those receiving vagal blockade lost 24% of their
gest functional roles for gastric nutrient-sensing receptors, excess weight in 1 year, versus 16% in the sham-operated
which may include roles in eating (see sect. IIIC). group. The mechanism underlying the efficacy of vagal
blockade is unknown. One possibility is that slowed gastric-
E. Glycemic Control emptying rate is involved (134, 405). In the patients de-
scribed above, gastric emptying was reportedly unchanged,
Gastric emptying contributes importantly to the regulation but because gastric emptying was measured after the pa-
of meal-related glycemia and, thus, to overall glucose ho- tients had undergone more than a year of vagal stimulation,
meostasis (472). For example, in both healthy subjects and it is possible that there was tachyphylaxis of an earlier effect
patients with T2DM, intersubject variability in emptying of (658). In other studies, vagal blockade increased ghrelin
an oral glucose load accounted for significant amounts of secretion and reduced secretion of CCK and GLP-1 (153,
the variability in plasma glucose increments (342, 470). In 154), effects that presumably would oppose any decrease in
addition, pharmacological manipulation of gastric empty- eating. An alternative hypothesis that deserves investigation
ing of a solid-liquid mixed-nutrient meal produced corre- is that vagal blockade reduces gastric accommodation dur-
sponding glycemic changes in patients with T2DM (285). ing meals, leading to increased distension and early satia-
Variation in factors that affect gastric emptying, such as tion. Because the blockade prevents vagal afferent signal-
decreasing dietary fiber content (369, 771), would presum- ing, this hypothesis requires that distension is adequately
ably increase the relative contribution of gastric emptying sensed by spinal-visceral afferents (82, 146).
to meal-related glycemia; conversely, manipulating post-
gastric factors, such as incretin-hormone secretion, would
reduce it. Small intestinal nutrient transport also may affect G. RYGB
meal-related glycemia. For example, pharmacological slow-
ing of intestinal flow of intraduodenally infused glucose Due to a greatly reduced gastric lumen (FIGURE 1), only a
slowed glucose absorption and reduced blood glucose fraction of the normal gastric volume can be accommo-
(137). dated, and antral trituration and pyloric control of empty-
ing are absent after RYGB. As a result, RYGB markedly
F. Obesity accelerates gastric emptying of liquids and solids (although
emptying of small, solid meals with volumes not exceeding
In several small-scale studies, gastric emptying was compa- the pouch volume may be slower) (213, 244, 339, 518, 536,
rable (562, 681), faster (295, 794, 797), or slower (338, 802, 808). This, in turn, often leads to bloating, nausea, and

STEINERT ET AL.
dumping in RYGB patients (307, 377, 545, 695, 745). Glu- amus (Arc) (184, 398, 524, 597, 742, 799, 826). Ghrelin
cose solutions, as used in glucose-tolerance tests, may O-acyltransferase (GOAT) catalyzes the conversion of
empty almost immediately in RYGB patients, leading to the ghrelin into its biologically active acylated forms, octanoyl-
appearance of ⬃300 kcal in the jejunum within 1–2 min and decanoyl-ghrelin (together referred to as acyl-ghrelin,
(544). Such rapid increases in small intestinal nutrient con- in contrast to unacylated or des-acyl-ghrelin). GOAT phys-
tent are likely to contribute to the increased meal-related iology has emerged as an important modulator of ghrelin
secretion of CCK, GLP-1, PYY(3–36), and insulin after function (58, 389, 524, 847). Less than 10% of circulating
RYGB, as described in the next sections. For example, in- ghrelin is acyl-ghrelin, which together with the difficulty in
fusion of glucose at a high physiological rate (4 kcal/min) assaying it, complicates studies of endogenous ghrelin (390,
into the Roux limb of RYGB patients and into the duode- 596, 707). The ghrelin receptor was described in 1996 as
num of healthy subjects elicited comparable increases in the growth hormone-secretagogue receptor-1A (GHSR1A)
GLP-1, whereas oral glucose loads (200 kcal/150 ml) pro- (348). It is widely expressed peripherally and centrally (398,
duced larger GLP-1 responses in the RYGB patients (544). 524, 799). Des-acyl-ghrelin has little affinity for GHSR1A
but may have metabolic effects via other receptors (524).
Three additional studies reveal further contributions of
RYGB-induced alterations of GI function to changes in eat-
ing and body weight: 1) faster pouch emptying on postop- B. Secretion
erative day 1 was associated with a ⬃4 kg increase in 1 year
weight loss (21); 2) pouch size was negatively correlated Plasma concentrations of total and acyl-ghrelin increase
with weight loss after 6 months and 1 year (626); and 3) before meals, decline precipitously after meals, and then
thresholds for detection of inflation of a balloon placed in increase gradually until the next meal (173, 326, 707). For
the Roux limb were negatively correlated with spontaneous example, when acyl-ghrelin was sampled frequently
meal sizes 6 months and 1 year postoperatively (81). Re- throughout the day in subjects adhering to a controlled
learning to eat comfortably is likely to be important in some sleep-wake, activity and meal protocol (707), acyl-ghrelin
of these effects, but such learning has not yet been studied maxima were ⬃110 pM before breakfast and ⬃100 pM
much in either humans (108, 177) or animals (424, 690). before lunch and dinner, and post-meal minima were ⬃70
For example, a questionnaire follow-up indicated that meat pM. Importantly, the ratio of circulating acyl- to total ghre-
was the food most often linked to food aversions after lin may change around meals (707). Because ghrelin’s
RYGB (288), which may be due to the challenge of digest- plasma half-life is ⬃30 min (20, 800), postprandial acyl-
ing meat without a stomach. ghrelin dynamics presumably primarily reflect inhibition of
secretion. There is also a gradual decrease in acyl-ghrelin
after midnight, which probably reflects an inhibitory effect
H. Summary of sleep; the pre-breakfast increase begins only after awak-
ening (707). These patterns suggest that habitual sleep-
GI motor function and gastric emptying are closely regu- wake cycles and the timing of breakfast modulate morning
lated. Neural gastric-volume detection contributes to the ghrelin levels. This complicates any definition of “basal”
inhibitory control of eating, and gastric emptying contrib- plasma ghrelin and indicates that across-group compari-
utes to meal-related glycemic control. CCK, GLP-1, and sons of pre-meal plasma ghrelin concentrations should con-
PYY(3–36) contribute to the control gastric emptying, and sider the times of sampling with respect to habitual meal
ghrelin may do so. Intestinal-nutrient sensing links the se- times. Average daily ghrelin levels might provide a useful
cretion of ghrelin, CCK, GLP-1, and PYY(3–36) to gastric alternative. Cummings et al. (173) reported 1) a correlation
emptying and gastric volume (FIGURE 5). Loss of normal of 0.95 between the 0930 h ghrelin level (i.e., the post-
gastric accommodation, food storage, food trituration, and breakfast minimum) and the 24 h ghrelin area under the
emptying are likely to play important roles in the effects of curve (AUC), and 2) a correlation of 0.87 between the 0600
RYGB on eating and glycemic control. h ghrelin level (the pre-breakfast minimum) and the 24 h
AUC, indicating that both measures accurately reflect the
III. GHRELIN integrated or average daily ghrelin level.
The mechanisms stimulating ghrelin secretion during

A. Introduction fasting are poorly understood. In one study, ghrelin levels
were elevated after a 3-day fast and did not change
Ghrelin is a 28-amino acid peptide hormone discovered in around meals, although the nocturnal increase was unaf-
1999. Ghrelin is produced by closed-type enteroendocrine fected (139). Autonomic efferents contribute to the stim-
cells in the oxyntic glands of the gastric fundus (184, 397) ulation of ghrelin secretion in both humans (107) and
(FIGURE 6A), as well as by some small intestinal enteroen- animals (346, 852). Cephalic-phase reflexes activated by
docrine cells, pancreatic-islet cells, and neurons in various the sight, smell, and taste of food (i.e., elicited by modi-
brain areas, including the arcuate nucleus of the hypothal- fied sham feeding) were reported to both stimulate (511,

A Ghrelin cells are closed-type B CCK, GLP-1 and PYY cells are open-type
Gastric Small-intestinal
1
lumen lumen
3 2
1 4
2
4 3
FIGURE 6. Schematic of the organization of ghrelin, CCK, GLP-1, and PYY entroendocrine cells. A: gastric
ghrelin cells (blue) are closed-type. Their apical aspects are enclosed by epithelial cells (tan) so that they have
no direct contact with the gastric lumen. 1) Neural signals provide the major stimulatory control of ghrelin
secretion. 2) Secreted ghrelin (red dots) diffuses through the lamina propria (yellow) into gastric capillaries
(salmon) and is transported into the hepatic-portal vein and systemic circulation. 3) Ghrelin cells express a
number of nutrient receptors, mainly on the basal and lateral aspects (orange ⬍). These are probably
stimulated mainly by metabolites reaching them by diffusion from the gastric capillaries through the lamina
propria, although some nutrients may reach them directly from the stomach. 4) CCK, PYY(3–36), perhaps
other small intestinal hormones, and other humoral stimuli reach ghrelin cells via the circulation and inhibit
ghrelin secretion. Paracrine signals (not shown) may also be involved. B: CCK, GLP-1, and PYY cells (blue) are
open-type, with direct contact with the small intestinal lumen. 1) Each expresses a number of nutrient
receptors, mainly on the apical and lateral aspects (orange ⬍). These are probably the major controls of
secretion of these hormones. The nutrient receptors expressed by ghrelin, CCK, GLP-1, and PYY cells are
listed in TABLE 4, which also indicates the extensive overlap in the nutrient receptors expressed by the these
cell types. 2) Secreted hormones (red dots) diffuse through the lamina propria (yellow) into small-intestinal
capillaries (salmon) and are transported into the hepatic-portal vein and systemic circulation. 3) Metabolites,
hormones, and other humoral factors reach CCK, GLP-1, and PYY cells by diffusion from mesenteric capillaries
through the lamina propria (yellow) or from nearby small-intestinal epithelial cells (tan). 4) Neural inputs also
control CCK, GLP-1, and PYY secretion.
512, 696) and inhibit ghrelin secretion (35) in humans. probably stimulated mainly by metabolites entering the
Time cues also increase pre-meal ghrelin levels in sched- laminal propria from the circulation, as discussed below.
ule-fed rats (180, 494). There is some evidence, however, that they can be stimu-
lated by gastric contents. Lu et al. (457), for example, found
Ghrelin secretion after meals is inhibited by GI signals that that mouse ghrelin cells express the free fatty acid receptor
are recruited rapidly by nutrient ingestion. Conditioned 4 (Ffar4), that fatty acids inhibited ghrelin secretion in
(167) and cephalic-phase reflexes (315) may contribute. vitro, and that intragastric lipid loads reduced serum ghre-
There appears to be no gastric phase to post-meal ghrelin lin levels in mice with ligated pylori. Similar results were
inhibition because 1) intragastric water or liquid-diet infu- obtained in rat gastric explants (22, 692). These data are
sions had no effect on ghrelin levels in rats when infusates inconsistent with the rat pyloric cuff data described above
were confined to the stomach with a pyloric cuff (558, 829), (558, 829), and relevant studies remain to be done in hu-
2) plasma ghrelin concentrations were reduced comparably mans. Few human enteroendocrine ghrelin cells express
by intragastric and intraduodenal glucose infusions in GNAT3, TAS1R1/TAS1R3, or FFAR4, although nearby
healthy-weight men and women (563, 719), and 3) in con- cells do, suggesting the possibility of a gastric paracrine
trast to most enteroendocrine cells, gastric ghrelin cells are chemosensory control of ghrelin secretion (825).
closed type, i.e., do not directly contact to the GI lumen
(FIGURE 6A). Nevertheless, gastric ghrelin cells express sev- The intestinal phase of post-meal ghrelin inhibition is well
eral nutrient-sensing receptors that may affect ghrelin secre- established (169, 248, 563, 640, 719). The critical site for
tion (207, 237, 311, 367, 457, 524, 824, 825) (TABLE 4, inhibition by glucose appears to be distal to the duodenum
which includes the full and the former names of the nutrient and proximal jejunum because ghrelin secretion (60 min
receptors discussed below). Because these are expressed AUC) was not inhibited by intraduodenal infusions of glu-
mainly on the basolateral aspects of ghrelin cells, they are cose that were limited to only the proximal 60 cm of the

STEINERT ET AL.
Table 4. Nutrient receptors expressed by enteroendocrine ghrelin, CCK, GLP-1, and PYY cells
Nutrient Receptor Ghrelin CCK GLP-1 PYY
CASR (CaR) X X X X
CD36 X
FFAR1 (GPR40) X
FFAR2 (GPR43) X X
FFAR3 (GPR41) X
FFAR4 (GPR120) X X X
GNAT3 (gustducin) X X
GPR119 X
HCAR1 (GPR81) X
LPAR5 (GPR93) X
SLC2A1 (GLUT1) X
SLC2A2 (GLUT2) X
SLC2A5 (GLUT5) X
SLC5A1 (SGLT1) X
SLC15A1 (PEPT1) X X
TAS1R1/TAS1R3 (T1R1/T1R3) X X
TAS1R2/TAS1R3 (T1R2/T1R3) X X
TAS1R3 (T1R3) X
The table is based on the evidence of receptor expression in mice, rats, or humans discussed in the text.
Former names of the receptors are given in parentheses. CaR, calcium receptor; CASR, calcium-sensing
receptor; CD36, thrombospondin receptor; FFAR, free fatty acid receptor; GLUT, glucose transporter;
GNAT3, guanine nucleotide-binding protein, alpha transducing 3; GPR, G protein-coupled receptor; HCAR1,
hydroxycarboxylic acid receptor 1; LPAR5, lysophosphatidic acid receptor 5; PEPT1 and SLC15A1, solute
carrier family 15 (oligopeptide transporter), member 1; TAS1R1 and T1R1, taste receptor, member 1;
TAS1R2 and T1R2, taste receptor, member 2; TAS1R3 and T1R3, taste receptor, member 3 (T1R1/T1R3).
Note that abbreviations are for the human genes, although many of the receptors indicated have been
identified on the respective enteroendocrine cells so far only in mice or rats.
small intestine to glucose by an inflated balloon, but was All three macronutrients inhibit ghrelin secretion after
inhibited when glucose was also allowed access to the more meals. Consumption of carbohydrate and protein reduced
distal small intestine (445). The underlying mechanisms are ghrelin levels during the next 3 h more than did isoenergetic
unknown. lipid loads (258, 510). Whether carbohydrates and proteins
differentially affect ghrelin secretion is less clear. 1) In over-
Circulating metabolites and hormones may also contribute weight and obese men, ⬃250 kcal oral loads containing
to the inhibition of ghrelin secretion. Intravenous glucose 80% energy as lactose, whey or casein reduced ghrelin lev-
infusion, alone or together with insulin, reduced ghrelin els more than similar glucose loads 120 –180 min after in-
levels under several conditions (254, 506, 526, 644, 688). gestion (96). 2) In healthy-weight and overweight men and
Insulin may be the key factor, as meals did not reduce ghre- women, ⬃500 kcal oral protein and glucose loads reduced
lin levels in patients with type 1 diabetes mellitus (T1DM) ghrelin levels similarly for ⬃3 h, but protein reduced ghrelin
in the absence of insulin therapy, but did so following rein- levels more effectively subsequently (258). 3) In healthy-
statement of basal euinsulinemia (526). In contrast to glu- weight women, no differences in ghrelin levels were de-
cose infusions, intravenous lipid infusions failed to affect tected during 24 h trials comparing a 10% protein-energy
plasma ghrelin levels (506). Increases in peripheral concen- diet, a 60% carbohydrate-energy diet, and a 30% protein-
trations of lactate and short-chain fatty acids resulting from and 40% carbohydrate-energy diet (427). Carbohydrate
colonic fermentation of poorly digestible carbohydrates type is also important: oral glucose reduced ghrelin levels
(46, 523, 753, 758) may be sensed by hydrocarboxylic acid less than lactose (96), but more than fructose (755). Because
receptor 1 (HCAR1) and FFAR2, respectively, because the none of the studies reviewed above assessed gastric empty-
corresponding receptors are expressed by gastric ghrelin ing, differential rates of small intestinal appearance of in-
cells in mice (237). Plasma lactate also increases following gested nutrients may have contributed as well as direct ef-
many meals (694, 734) as well as during exercise and hyp- fects of specific intestinal nutrient sensors.
oxia (135, 286, 815), and both exercise and hypoxia de-
crease plasma ghrelin levels in rats and humans (135, 815). Lipids and di- or polysaccharides require digestion to in-
Finally, circulating amino acids may inhibit ghrelin secre- hibit ghrelin secretion fully because tetrahydrolipstatin, a
tion via calcium-sensing receptor (CASR) (237). lipase inhibitor, and arcabose, an ␣-glucosidase inhibitor,

decreased the inhibition of ghrelin secretion by intraduode- changes in food hedonics rather than hunger, a hypothesis
nal lipid infusions and sucrose drinks, respectively (197, supported by neuropharmacological data in animals (211,
248, 250, 749). These studies also revealed that only fatty 370). For example, in rats and mice, injection of ghrelin into
acids with a chain length greater than or equal to C12 the ventral tegmental area, a reward area, activated dopa-
inhibit ghrelin secretion (197, 250). mine neurons, and injection of a ghrelin-receptor antago-
nist into the ventral tegmental area prevented the stimula-
The neuroendocrine reflexes mediating post-meal ghrelin tion of eating by peripheral ghrelin administration (4).
inhibition by intestinal nutrient sensing are poorly under-
stood. The vagus nerve seems unnecessary in rats because Animal studies also link ghrelin signaling to brain networks
vagotomy did not affect post-meal ghrelin inhibition in rats thought to be related primarily to homeostatic eating. For
(830). CCK and PYY(3–36) may be involved because intra- example, in mice, ghrelin administration into the Arc
venous infusions of each reduced plasma ghrelin levels in acutely stimulated eating and altered the activities of Arc
humans (61, 104, 198), whereas GLP-1 infusion did not neuropeptide Y, agouti-related peptide, and pro-opiomela-
(104). We are aware of only one test of the physiological nocortin neurons (145, 164, 810). Ghrelin also appears to
relevance of these potential endocrine controls of ghrelin act in the Arc to reduce serotonin 2C receptor-mediated
secretion: CCKA-receptor blockade abolished long-chain inhibition of eating (661). Finally, initial reports that the
fatty acid-induced ghrelin inhibition in healthy subjects, vagus nerve was required for ghrelin to stimulate eating (36,
suggesting that the mechanism involves CCK (197). Finally, 185, 186) were not replicated when a more selective lesion
although fasting plasma ghrelin levels correlated with basal method was used, which also supports a central action of
leptin levels (240), leptin infusion failed to reinstate normal ghrelin on eating (34).
meal-related ghrelin patterns in healthy-weight men who
had fasted 3 days (139). An unresolved challenge to the hypothesis that ghrelin sig-
nals hunger is that transgenic mice with reduced ghrelin
signaling do not display a tonic increase in eating (524).
C. Eating Some such transgenics do develop obesity, especially when
fed a high-fat diet (524), but this may be secondary to
Changes in plasma ghrelin levels around meals fulfill crite- decreases in fatty acid oxidation and increases in lipid de-
rion 1 of TABLE 2 for an endocrine role in hunger signaling. position in response to changes in autonomic nervous sys-
1) Plasma ghrelin levels increase progressively before meal tem activity (484, 524, 572, 757). As a consequence, ghrelin
onset and fall precipitously afterwards (173, 276, 390, 707, is currently considered to be a stronger candidate for the
778). 2) Hunger ratings were closely related to the drops development of pharmacotherapies for metabolic disease
and subsequent increases of total ghrelin levels between than for overeating.
lunch and a spontaneous dinner in healthy-weight, time-
blinded men (171) as well as between breakfast and a lunch D. Glycemic Control
offered at a set time in overweight and obese men and
women (276). 3) Breakfast-to-lunch intermeal intervals in Ghrelin may affect glycemic control by accelerating gastric
healthy-weight, time-blinded men who were served dinner emptying, inhibiting insulin secretion, or stimulating secre-
upon request were correlated with post-breakfast decreases tion of glucagon or other counterregulatory hormones
in total ghrelin and with the AUC of the breakfast-to-lunch (106, 152, 170, 202, 524, 530, 750, 799). In one study,
ghrelin response (84) [although these correlations were not intravenous infusion of a near-physiological dose of 0.3
detected in non-time-blinded men (124)]. 4) Ghrelin con- pmol·kg⫺1·min⫺1 ghrelin, reduced insulin levels in response
centrations at meal onset correlated with meal size in to intravenous glucose infusion and increased growth hor-
healthy-weight and overweight men and women offered mone and cortisol, but not glucagon, epinephrine, or nor-
lunch at a set time (276). Tests of ghrelin infusions, how- epinephrine, levels (767). Studies in mice indicate that the
ever, have hitherto failed to fulfill criterion 3 of TABLE 2. insulin-inhibitory effect of ghrelin is mediated by a direct
Intravenous infusion of 0.3 pmol·kg⫺1·min⫺1 ghrelin, a action on pancreatic ␤-cells (208, 413). The modulation of
near-physiological dose (TABLE 3), that began 1 h after a ghrelin acylation by dietary levels of C8 and C10 fatty acids
standard meal did not affect subjective hunger, the sponta- may provide a mechanism for brain nutrient sensing and the
neous intermeal interval, or the size of the following spon- neural regulation of glucose metabolism (389), although
taneous meal (444). Pre-meal infusion of 1–5 pmol· given the low levels of these fatty acids in most diets, this
kg⫺1·min⫺1 ghrelin, however, did stimulate eating in two seems unlikely to be a physiological endocrine effect under
tests in which meals were offered at set times (221, 839). most conditions.
Interestingly, supraphysiological ghrelin infusions also in-
creased neural activity in response to pictures of food, as E. Obesity
detected by functional magnetic-resonance imaging (fMRI),
in brain regions associated with food reward (284, 465). GHRL polymorphisms were associated with BMI variation
This suggests that ghrelin may affect eating primarily via in several human populations (430). Although significant,

STEINERT ET AL.
the effects are quite small [for example, a GHRL polymor- reported that in obese subjects who had elevated fasting
phism at rs35683 accounted for ⬍0.3% of the variance in ghrelin levels and no post-meal ghrelin drops, RYBG ini-
BMI in a sample of 2,000 European-Americans (430)], and tially reduced fasting ghrelin, but that by 1 year post-
the functional pathways that contribute to the effects are RYGB, fasting ghrelin levels were no longer reduced and
unknown. there were typical post-meal drops. Such gradual normal-
ization of ghrelin secretion after RYGB may result either
Fasting plasma ghrelin levels are decreased in obese subjects from weight loss or from dynamic adaptation of the GI tract
and increased by diet-induced weight loss (174, 240, 390, (678). RYGB increased ghrelin levels in some rodent studies
779). Because obesity increases fasting insulin levels, the (31, 780, 854), but decreased them in others (731, 735).
inhibitory effect of insulin on ghrelin secretion (see sect. Stylopoulos et al. (731) suggested that this apparent dis-
IIID) may contribute to obesity’s effect on fasting ghrelin. crepancy may be attributable to an effect of the initial rapid
Shiiya et al. (688), however, did not detect any effect of postsurgical weight loss to increase ghrelin levels combined
T2DM on fasting plasma ghrelin in obese subjects. Post- with a sustained decrease in ghrelin secretory capacity due
prandial drops in plasma ghrelin were reduced in some to the gastric resection. Interestingly, in their rat model,
(239, 240, 497, 574), but not all (103, 174, 403), studies of weight loss 3 months after surgery was correlated with the
obese subjects. pre- to postsurgery decrease in ghrelin levels (731). In an-
other rat study (691), in which there were no consistent
We are aware of one study of the effect of ghrelin on eating changes in pre-meal ghrelin levels tested 12–16 wk after
in obese humans (221), which was inconclusive. Acute in- RYGB, ghrelin levels decreased more after meals in RYGB
travenous infusions of supraphysiological doses of ghrelin than control rats, and the magnitude of the effect was cor-
(1 and 5 pmol·kg⫺1·min⫺1) appeared to increase eating related with weight loss.
more in obese than in healthy-weight subjects, but whether
the differences were statistically significant was not tested.
G. Summary
F. RYGB FIGURE 7 summarizes ghrelin physiology around meals.

Ghrelin secretion increases during fasting and is inhibited
Fasting and post-meal ghrelin levels are reduced in the first by cephalic- and intestinal-phase reflexes during and after
2 wk after RYGB, but the longer-term effects are contro- meals. Sensing of all three macronutrients contributes to the
versial (174, 310, 390, 403, 574, 712). Peterli et al. (574) intestinal phase of ghrelin inhibition. Pre-meal ghrelin levels
Stomach
FIGURE 7. Some features of ghrelin

physiology. Ghrelin is secreted from closed-
type enteroendocrine cells (blue) dispersed
1 Eating in the epithelial layer (tan) of the gastric
Ghrelin mucosa. Ghrelin diffuses through the lam-
ina propria (yellow) and into gastric capillar-
ies (salmon). 1) Ghrelin’s potential physio-
logical effects include acting in the brain to
Gastric emptying stimulate eating, acting in the stomach to
Small intestine stimulate gastric emptying, and acting on
the pancreatic ␤-cells to inhibit insulin se-
3
cretion. 2) Ghrelin secretion is stimulated
mainly by neural controls. 3) Feedback
Insulin secretion from small-intestinal nutrient sensing, me-
CCK
PYY(3-36) diated in part by open-type CCK and PYY(3–
Nutrients 36) cells, inhibits ghrelin secretion during
and after meals.

are correlated with hunger sensations and meal size, but if pM at 60 –90 min. Similarly, using the state-of-the-art
ghrelin has a causal endocrine role in hunger is unclear. RAPID method, Eysselein et al. (242) found a 1,600 kcal
Ghrelin may contribute to glycemic control via several mixed-nutrient meal increased plasma CCK from a fasting
mechanisms. Indeed, it has been hypothesized that ghrelin’s level ⬃2.5 to ⬃7 pM at 60 min. A number of studies involv-
major function is to prepare the organism for the nutrient ing isoenergetic loads of highly digestible nutrients that
repletion and storage (389, 524). Studies to date of ghrelin were infused intraduodenally to control gastric-emptying
physiology in obese individuals and after RYGB have not effects indicate that, with respect to both peak values and
produced consistent results. Ghrelin antagonists and in- AUC, 1) oral lipids stimulate CCK secretion most per kcal,
verse agonists suitable for human use (78, 125) may soon proteins are intermediate, and carbohydrates stimulate
resolve many of these outstanding questions. CCK secretion least; and 2) plasma levels increase in 10 –15
min (327, 337, 446, 584, 641, 682).
IV. CHOLECYSTOKININ
Hydrolysis of proteins and triglycerides is required for nor-
mal CCK secretion (55, 159, 247, 325, 479, 718). Addi-
A. Introduction tionally, fatty acids with chain length greater than or equal
to C12 stimulate CCK secretion much more than fatty acids
CCK cells are open-type cells, i.e., their apical surfaces are less than C12 (249, 479, 486, 487), and less saturated long-
exposed to the intestinal lumen (FIGURE 6B). Initial electron chain fatty acids stimulated CCK secretion more than
microscopy and immunocytochemistry studies suggested highly saturated fatty acids (67). Carbohydrate digestion
that they were a unique species of enteroendocrine cells, may not be required, as the ␣-glucosidase inhibitor acar-
called I-cells (590). Contemporary methods, however, indi- bose had little or no effect on the CCK response to mixed-
cate that, at least in rodents, many enteroendocrine CCK nutrient meals (236, 751, 784).
cells also express and secrete ghrelin, GLP-1, PYY, GIP,
neurotensin, or secretin (231, 303, 597, 738, 742). In hu- Consistent with the higher density of enteroendocrine CCK
mans, swine, and rats, enteroendocrine CCK cells are cells in the proximal small intestine, intraduodenal glucose
densely expressed in the duodenum and proximal jejunum, infusions that were prevented from transiting more than 60
less dense in the distal jejunum, and sparse in the ileum (45, cm distal to the pylorus by an inflated balloon stimulated
478, 503). CCK secretion as much as infusions done without balloon
inflation (445). This is likely also to be the case for fat and
CCK circulates predominantly in a 58-amino acid form protein. Intraileal lipid infusion also increased CCK secre-
(CCK-58) (243, 431, 612, 722). Importantly, many CCK tion (466), but whether this was due to a direct action on
assays that involve plasma formation recover ⬍20% of en- ileal CCK cells or to an indirect, presumably endocrine,
dogenous CCK, so they provide accurate relative, but not distal-to-proximal reflex is unknown.
absolute, levels (243, 431, 722). Additionally, most tests of
exogenous CCK use CCK-8, which is rare or absent in the Intraluminal nutrients directly and indirectly stimulate
plasma. This may be important because the liver clears CCK secretion. Direct nutrient effects are mediated by a
CCK-8 faster than larger forms (287, 404) and CCK-8 had variety of nutrient receptors expressed on the apical surface
slightly different effects than CCK-33 or CCK-58 in animal of CCK cells (FIGURE 6B AND TABLE 4, which includes the
models (607, 608), including in tests of eating in rats (232, full and the former names of the nutrient receptors dis-
279, 281). cussed below). In humans, free fatty acids act on FFAR1
(443), FFAR4 (752), and the fatty-acid transporter CD36
There are two CCK receptors, CCKAR (or CCK1R) and
(733); oligopeptides and amino acids act on CASR (161,
CCKBR (CCK2R) (216, 514, 515, 612). CCKAR is more
328, 811), LPAR5 (149), TAS1R1/TAS1R3 (160, 182,
abundant peripherally than centrally and requires the seven-
543) and, perhaps, SLC15A1 (183). The presence of tran-
amino carboxy-terminal segment and sulfation of the ty-
scripts for TAS1R2/TAS1R3 and GNAT3 on CCK-secret-
rosine residue at position 7 for full activation. CCKBR, or
ing mouse enteroendocrine STC-1 cells suggests that sweet-
the gastrin receptor, is sensitive to unsulfated CCK hexa-
receptor signaling may contribute to glucose-induced CCK
peptides and is abundant both peripherally and centrally,
release in mice (228, 849). This may not be the case in
where CCK-8 is a neurotransmitter.
humans, however, because intragastric and intraduodenal
infusions of the sweet-receptor inhibitor lactisole that re-
B. Secretion duced glucose-induced GLP-1 and PYY secretion did not
affect CCK secretion (275). Intraluminal nutrients also
Mixed-nutrient meals increase CCK secretion. Using a well stimulate CCK secretion indirectly via the CCK-releasing
validated radioimmunoassay, Rehfeld et al. (609) found factors “pancreatic monitor peptide” and “intestinal lumi-
that a 1,470 kcal mixed-nutrient meal increased plasma nal CCK-releasing factor” (456, 504, 812). This occurs in
CCK from a fasting level of ⬃1 to ⬃3 pM at 30 min and ⬃5 part due to binding of proteases to proteins and lipids,

STEINERT ET AL.
which reduces protease-induced degradation of CCK-re- obesity (192, 473, 501), suggesting that endogenous CCK is
leasing factors (168, 432). also important for the tonic control of eating. 2) fMRI
following intragastric lauric acid loads with or without
loxiglumide indicated that CCK signaling is crucial for nor-
C. Eating
mal brain responses to this fatty acid (419) (because lauric
CCK is the best-established GI endocrine satiation signal in acid is uncommon in Western diets, the generality of this
humans. First, in three studies (54, 299, 438), intravenous finding is uncertain). 3) CCK doses substantially above
infusions of physiological doses of CCK reduced meal size physiological (i.e., ⬃1.8 to ⬃3.5 pmol·kg⫺1·min⫺1, TABLE
3) inhibited eating without eliciting adverse effects (100,
without adverse physical or subjective effects in men and
women, which fulfills criteria 3 and 5 of TABLE 2. The study 269, 290, 391). Interestingly, CCK infusions reduced meal
by Lieverse et al. (438) is especially interesting because the size ⬃30 –50% in these studies without affecting fullness or
test food, bananas, did not elicit CCK secretion under their other meal-related sensations compared with the control
conditions (440), so that the infused CCK did not synergize condition, suggesting that CCK had an effect on conscious-
with endogenous CCK, as probably happens in most satia- ness indistinguishable from the presumably more complex
tion tests. Second, intravenous infusions of the CCKAR afferent activation produced by the larger quantity of food
antagonist loxiglumide increased premeal hunger feelings, eaten in the control condition. 4) In most of these studies,
reduced fullness feelings during the meal, increased meal CCK infusions began after a small preload to capitalize on
size, and blocked the satiating effects of intraduodenal lipid the synergy between gastric mechanoreception and CCK
infusion (70, 439, 480), which fulfills criteria 4 and 6 of (528), described in section IIC.
TABLE 2. These studies, summarized in FIGURE 8, have
made CCK paradigmatic for the study of the endocrine Attempts to relate endogenous CCK levels with subjective
control of eating. measures of appetite have been less informative than studies
of manipulation of CCK. 1) In the sole study of intrameal
In addition, 1) human CCKAR polymorphisms are associ- effects, plasma CCK increased more during meals in women
ated with increased meal size, increased food intake, and than in men, but hunger and fullness ratings did not differ;
A g B kcal C kcal
500 2500 2500
*
400 2000 2000 *
+
*
Meal Size
Meal Size
Meal Size
300 1500 1500
200 1000 1000
100 500 500
0 0 0
IV SAL CCK IV SAL SAL LOX IV SAL LOX
ID SAL FAT FAT
FIGURE 8. Evidence that endogenous CCK signals satiation in healthy humans. A: intravenous infusion of a
physiological dose of CCK inhibited eating. Ten healthy-weight women [body mass index (BMI) 22 ⫾ 3 kg/m2]
and 8 obese women (BMI 39 ⫾ 2 kg/m2) received 60 min intravenous (IV) infusions of 0.24 pmol·kg ideal body
weight⫺1·min⫺1 CCK-33 or saline (SAL) beginning at 0800 after an overnight fast. At 0900, a 132 kcal
preload of bananas was served, and at 0915, a banana-shake meal was served in excess; bananas were used
because they did not elicit CCK secretion. CCK significantly reduced meal size (*) without physical or subjective
side effects. [From Lieverse et al. (438), with permission from BMJ Publishing Group Ltd.] B: the CCKA
receptor antagonist loxiglumide (LOX) antagonized the satiating action of endogenous CCK stimulated by
intraduodenal (ID) infusion of a fat emulsion. Healthy-weight adult males began a midday lunch buffet 4 h after
a standard breakfast, 90 min after onset of an IV infusion of 10 ␮mol·kg⫺1·h⫺1 LOX or SAL, 60 min after an
ID infusion of 0.4 ml/min corn oil (FAT) or SAL, and 20 min after an oral preload of 400 ml of a low-fat banana
milkshake. Infusions were continued throughout the meal. ID fat infusion significantly reduced the size of the
lunch meal (⫹), and that this was reversed by LOX (*); no physical or subjective side effects occurred in any
condition. [From Matzinger et al. (480).] C: antagonism of CCK signaling with the CCKA receptor antagonist
LOX stimulated eating. Healthy-weight adult males began a midday lunch buffet 4 h after a standard breakfast
and 60 min after beginning an IV infusion of 22 ␮mol·kg⫺1·h⫺1 LOX or SAL. Infusions were continued
throughout the meal. LOX significantly increased meal size (*) without physical or subjective side effects. [From
Beglinger et al. (70).]

women gave higher ratings of “sickness” early in the meal, the satiating effect of exogenous CCK (516). As little or no
but not later when CCK levels increased more, nor did they food reaching the pylorus is digested sufficiently to stimu-
spontaneously report illness or display signs of illness (549). late CCK secretion and the CCKAR are localized in the
The small sample size (four of each sex) further limits this muscle layer rather than the mucosal layer (565), the pyloric
study. 2) Postprandial CCK levels and hunger and fullness contribution to CCK satiation is likely to be endocrine. 2)
ratings were significantly correlated in a group of nine men, Vagotomy studies suggest that endocrine CCK may also act
but the relationships were not detected in all individuals (3 in the brain to inhibit eating (615, 850). For example, in-
of 9 for hunger and 4 of 9 for fullness) (260). 3) Meals travenous infusions of devazepide, which enters the brain,
containing different fats differentially increased postpran- stimulated eating after vagotomy, whereas infusions of a
dial plasma CCK levels in eight women, and these were larger-molecule CCKAR antagonist that penetrates periph-
mirrored by subjective hunger and fullness ratings; but nei- eral capillaries, but not the blood-brain barrier, did not
ther CCK responses nor appetite ratings differed in seven (615). The site of the brain CCKAR mediating these effects
men (119). 4) Meals containing different fat-to-carbohy- is not known. The NTS (83, 330), to which vagal afferents
drate ratios differentially increased postprandial plasma project, and the dorsomedial nucleus of the hypothalamus
CCK levels in 16 overweight and obese men and women, (79) are candidates.
but no associations with subjective appetite were detected;
there was also no difference in the size of meals offered 3 h Whether CCK’s physiological satiating effect in humans
later, but by this time CCK levels had returned to basal involves local or endocrine action is unclear. That infusions
(277). Because CCK appears to signal satiation, but not mimicking systemic levels reached during meals are suffi-
postprandial satiety, it is unfortunate that there are not cient to reduce eating even when endogenous CCK secre-
more studies of the relationships among differential in- tion is minimized (438, 440) suggests, but does not prove,
trameal plasma CCK levels, appetite, and meal size. that local signaling is not responsible. This is because GI
hormones diffuse down a steep concentration gradient from
Reproductive physiology may affect CCK satiation. the lamina propria into the mesenteric veins and are then
Women spontaneously eat progressively less during the fol- successively diluted in the hepatic-portal circulation and
systemic circulation (FIGURE 3). Thus, although the exact
licular phase of the menstrual cycle, reaching a nadir in
difference between lamina propria and systemic CCK con-
daily food intake during the periovulatory phase that is
centrations is unknown, it seems likely that physiological
⬃275 kcal/day less than the luteal-phase maximum (38).
intravenous CCK infusions are not sufficient to reproduce
Rats and mice also display a decrease in food intake during
the CCK concentrations in the lamina propria that occur
the periovulatory phase, due in part to an increase in the
during meals.
satiating potency of CCK related to estrogen signaling in the
nucleus of the solitary tract (NTS) (38).
D. Glycemic Control
Studies in rodents suggest that CCK inhibits eating via both
local and endocrine modes of action. In support of local No direct role has been established for CCK in glycemic
action, intravenous infusion of the small-molecule CCKAR control in humans. Infusion of a physiological CCK-8 dose
antagonist devazepide, which presumably diffused from the (0.4 pmol·kg⫺1·min⫺1) reduced plasma glucose after an
capillaries into the small intestinal-lamina propria, in- oral glucose load, but not after an intraduodenal glucose
creased food intake, but infusions of a CCK antibody, infusion that mimicked the gastric-emptying rate of the oral
which would not escape the vasculature so as to selectively glucose (437), suggesting that CCK reduces blood glucose
block endocrine effects, did not (616). Infusion studies in- indirectly via inhibition of gastric emptying. In two studies,
dicate that the most likely physiological site of CCKAR however, the CCKAR antagonist loxiglumide failed to af-
mediating satiation is the proximal small intestine (165, fect plasma glucose despite accelerating gastric emptying
814). In addition, the satiating action of intraperitoneal (263, 323). Physiological levels of CCK do not appear to
injections of CCK is mediated by vagal afferent fibers (165, lower blood glucose by increasing insulin secretion because
426, 704, 705), and most small intestinal vagal afferents infusion of 0.2– 0.4 pmol·kg⫺1·min⫺1 CCK-8 did not in-
terminate within the crypt and villous lamina propria, but crease the insulin response to co-infusion of glucose (637).
not in close apposition to enteroendocrine CCK cells, indic- Physiological infusions of CCK did, however, increase the
ative of a paracrine action (77). Nevertheless, some vagal insulin response produced by amino-acid infusions in two
afferents terminate with 5 ␮m of CCK cells (77), and CCK (324, 637) of three (253) studies. But several attempts to
neuropods appear to signal via enteric glial cells (90) (de- demonstrate a direct insulinotropic effect of CCK using
scribed in section IB3 and FIGURE 3) so that neurocrine or various CCKAR antagonists and various nutrient stimuli
neuropod satiation signaling is also possible. failed (65, 263, 323, 324, 400, 434, 547, 667, 673).
Other data in rats and mice support an endocrine mode of CCK secretion was reduced in patients with longstanding
action. 1) CCKAR in the pyloric muscle layers contribute to T2DM (112, 636), perhaps due to the autonomic neuropa-

STEINERT ET AL.
thy and reduced rates of gastric emptying typical of these the satiating effect of exogenous CCK, and the de-satiating
patients (344). CCK-8 infusion further slowed gastric emp- effect of devazepide were reduced in rats fed a high-fat diet
tying and improved postprandial insulinemia and glycemia (225, 739).
in patients with T2DM (18, 580, 636). Thus CCK agonists
may be useful in diabetes therapy. Reports that rats that received intraperitoneal infusions of
CCK during every spontaneous meal for 6 days (821) and
Studies in rats indicate that CCK affects glucose metabolism mice with transgenic null mutations of Cckar (402) in-
by reducing hepatic glucose production via a vagal-vagal creased meal frequency and failed to gain weight contrib-
reflex (98, 99, 147, 605). CCK was infused intraduodenally uted to the views that CCK (and by extension other GI
in amounts that failed to increase CCK concentration in the hormones) does not contribute significantly to tonic energy
hepatic-portal vein to mimic the local action of CCK in the homeostasis and is a poor candidate for obesity pharmaco-
lamina propria, thus providing unique evidence for a para- therapy. [The OLETF rat, which also bears a Cckar null
crine action. This method seems feasible for human studies mutation, is obese, but this is apparently due to loss of
and may lead to better understanding of the relative roles of
hypothalamic Cckar rather than vagal Cckar (79).] Recent
local and endocrine signaling in GI hormone function.
preclinical data are more promising. First, stabilized forms
of CCK that resist enzymatic degradation reduced food in-
E. Obesity take and body weight in various mouse obesity models
(357, 359, 582). Second, native and stabilized CCK and
Whether obesity affects CCK secretion is controversial. CCKAR agonists increased the anorectic and weight-low-
Fasting CCK levels were reduced in obese subjects in one ering actions of a GLP-1 receptor agonist, amylin, leptin, or
study (57), but not two others (103, 725). CCK responses to amylin plus leptin in various rat and mouse obesity models
intraduodenal oleic acid infusions tended to be delayed and (358, 776, 777), as did a CCK/GLP-1 agonist hybrid pep-
reduced in overweight or obese compared with healthy- tide (360). These promising results suggest that increased
weight subjects in one study (725), but CCK responses to CCK signaling may contribute effectively to obesity phar-
high-fat, high-carbohydrate, and high-protein meals were macotherapy.
comparable in obese and healthy-weight subjects in another
(103), and CCK responses to ingestion of high-fat meals
were larger in obese than healthy-weight subjects in a third F. RYGB
study (261). Whether these contrasting results were due to
differences in the specific nutrient stimuli used, in gastric CCK has not been a focus of RYGB research because RYGB
emptying, which was not assessed, or other factors is not prevents ingesta from contacting the majority of CCK-se-
known. creting cells. Nevertheless, intraileal lipid infusions in-
creased CCK secretion in healthy-weight subjects (466),
Some defects in CCK signaling can lead to obesity. As men- and postprandial CCK levels were normal (383, 622, 634)
tioned above, human CCKAR polymorphisms are associ- or increased (364, 574) following RYGB. For example, Pe-
ated with increased meal size, increased food intake, and terli et al. (574) found that CCK levels 30 min after a mixed-
obesity (192, 473, 501), suggesting that CCK-signaling de- nutrient meal were increased approximately twofold 1 wk,
fects can contribute to obesity etiology. In addition, allelic 3 mo, and 1 yr after RYGB. That the increase occurred just
variations in CCK were significantly more prevalent in
1 wk post-RYGB suggests that it does not require prolifer-
obese persons who habitually ate very large meals than
ation of CCK cells. The larger increases at later points may
those who did not (the “extreme discordant phenotype”
be related to the proliferation of CCK cells, which was
approach) (192).
reported in the Roux and common limbs of RYGB rats
We know of only one study comparing the satiating action (525). The effect of RYGB on CCK secretion is an interest-
of CCK infusions in healthy-weight and obese humans ing and under-researched phenomenon that may lead to
(438). No difference was obtained (infusion of 0.24 new opportunities for obesity therapy.
pmol·kg⫺1·min⫺1 CCK-33 reduced meal size ⬃18% in 10
healthy-weight women and ⬃20% in 8 obese women). RYGB reduced food intake and body weight in obese
OLETF rats (305), indicating that Cckar signaling is not
Obesity produced by high-fat feeding may interfere with necessary for some response to RYGB in this model. As no
CCK satiation. 1) CCK injections and balloon distension in ad libitum-fed, genetically normal RYGB rats were in-
isolated jejunal segments elicited smaller vagal-afferent cluded in the experiment, however, it is unclear whether the
electrophysiological responses in mice made obese by feed- OLETF rats were normally responsive to RYGB. We know
ing a high-fat diet than in chow-fed mice (181). 2) The CCK of only one test of acute CCKAR antagonism in RYGB rats
responsivity of vagal afferents was reduced in high-fat fed, (37), which failed to reveal any effect of RYGB on endoge-
leptin-resistant rats (193). 3) Fat-induced CCK secretion, nous CCK satiation.

G. Summary CCK 1 Satiation
CCK is secreted in response to the products of carbohy-

drate, lipid, and protein digestion. It has been clearly estab-
lished as a satiation signal in humans and may contribute to
the control of meal-related glycemia both indirectly, via its
effect on gastric emptying, and directly via control of he-
patic glucose production. The satiating effect in humans
may result from both local and endocrine actions, although
the latter appear more likely. These actions of CCK are
summarized in FIGURE 9. Pathophysiology of CCK signal-
ing may contribute to overeating, to obesity and T2DM in 2 Meal-related
glycemia
some patients, and to early satiation after RYGB. Preclini-
cal studies indicate that CCK is a candidate for obesity Digested
pharmacotherapy, especially in combination with other en- nutrients
docrine-based therapies.
V. GLUCAGON-LIKE PEPTIDE-1
A. Introduction
3 Gastric emptying
GLP-1 is secreted by open-type enteroendocrine cells (FIG-
URE 6B), originally identified as L cells (114, 589), located
in both the small and the large intestine (336, 597). Most
GLP-1 cells in the distal jejunum and ileum coexpress and
secrete PYY; in addition, some GLP-1 cells coexpress CCK,
GIP neurotensin, or secretin (231, 303, 568, 597, 738,
742). GLP-1 is also produced by a small group of neurons
located in the NTS (72, 128, 222, 336). Two equipotent
molecular forms circulate, GLP-1(7–37) and GLP-1(7- FIGURE 9. Some features of CCK physiology. CCK (red dots) se-
36NH2); the latter predominates in humans. Dipeptidyl cretion is stimulated by the digestive products of all three macronu-
peptidase-4 (DPP-4), a proline/alanine-specific peptidase trients acting on nutrient receptors on the apical aspects of en-
found on the luminal surface of capillary endothelial cells, teroendocrine CCK cells (blue) dispersed in the epithelial layer (tan)
of the small intestinal mucosa. CCK acts in an endocrine mode by
in the liver, and in the blood, rapidly degrades active GLP-1 diffusing through the lamina propria (yellow) and into intestinal cap-
to inactive forms, GLP-1(9 –37) and GLP-1(9-36NH2). In illaries (salmon) to reach distant target organs (red arrows), or acts
swine, only ⬃25% of active GLP-1 secreted from the intes- locally. 1) CCK’s physiological effects include stimulating satiation.
tine reaches the portal circulation, and only ⬃10 –15% This may occur via endocrine actions in the pyloric area of the
reaches the systemic circulation (336). stomach that produce signals relayed to the brain via vagal afferents
(green arrow) or via local actions on vagal afferents in the lamina
propria. An endocrine action in the brain may also contribute. 2)
GLP-1 receptors (GLP-1R) are expressed in the GI tract, CCK lowers meal-related glycemia via an endocrine effect on gastric
pancreas, cardiac atrium, abdominal vagal afferents, and emptying and perhaps via a vagal-vagal reflex. 3) Similarly, CCK
many brain areas (28, 115, 128, 336, 450, 623, 783). In slows gastric emptying via a direct endocrine effect and perhaps via
some animals, GLP-1 degradation products appear to sig- a vagal-vagal reflex. Solid lines indicate well-established effects, and
dashed lines indicate less well established effects.
nal via non-GLP-1 receptors (766). Whether these peptides
have physiological functions in humans is not known.
the morning level between meals (130, 235, 322, 557, 681,
804, 805). For example, when healthy-weight men and
B. Secretion women ate 524 kcal breakfasts and, 4 h later, mixed-nutri-
ent lunches containing 511, 743, or 1034 kcal, active
Available GLP-1 assay methods usually yield similar rela- GLP-1 increased from ⬃5 pM to ⬃8, ⬃12, and ⬃16 pM,
tive changes, but often different absolute concentrations respectively, after 30 min and then decreased to ⬃7 pM
(49, 410). Due to the rapid degradation of active GLP-1, after 180 min (27).
GLP-1 secretion is best estimated by the sum of active and
inactive GLP-1 in plasma (336, 508). Plasma GLP-1 con- Oral loads of glucose and several other carbohydrates usu-
centrations are at their lowest levels after overnight fasts, ally result in monophasic increases in plasma GLP-1, with
increase rapidly during meals, and usually do not return to onsets after 5–15 min, peak values after 15–30 min, and

STEINERT ET AL.
initial values regained after 3– 4 h (130, 235, 322, 399, 663, gastric empting contributes to the control of GLP-1 secre-
714, 759, 793, 805). Oral fructose, however, was only tion.
about half as potent a GLP-1 secretogogue as oral glucose,
both on a molar basis (409) and when matched for per- The distal small intestine usually plays the leading role in
ceived sweetness (716). Oral protein and lipid typically pro- sustained GLP-1 secretion. This was first indicated by com-
duce slower-onset, more sustained increases than does glu- parisons of GLP-1 secretion and glucose absorption. The
cose (95, 122, 128, 131, 195, 235, 336, 442, 600, 762). Due threshold intraduodenal glucose infusion rate for sustained
to the complex patterns of GLP-1 secretion described be- increases in plasma GLP-1 was between 1 and 2 kcal/min in
low, however, it is unclear whether any macronutrient two studies (663, 774) and between 2 and 4 kcal/min in
should be considered to be the most potent GLP-1 secreta- another study (583). Because the absorptive capacity of the
gogue. Both fasting and glucose-stimulated GLP-1 secretion duodenum and first 25–30 cm of jejunum is ⬃0.9 –1.4 kcal/
are pulsatile, with a period of ⬃8 min (50); the controls and min (334, 505, 575), glucose probably reached the more
consequences of this are not known. distal jejunum in these studies only when at least ⬃1.5
kcal/min glucose was infused, which suggests that stimula-
GLP-1 levels after mixed-nutrient meals sometimes display tion of more distal GLP-1 cells is required to elicit sustained
biphasic patterns (130, 235, 604), with secondary peaks GLP-1 secretion. Two experiments confirm this suggestion.
after 60 –120 min. Differences in rates of gastric emptying The first (159) involved intraduodenal infusion of 3.5 kcal/
and other differences in digestibility of the meal compo- min glucose 2 cm distal to the pylorus, aspiration of the
nents are likely to contribute to this, but are not their sole intestinal contents 60 cm distal to the pylorus, inflation of
cause because biphasic patterns also occurred after oral an occluding balloon just distal to the aspiration site, and
loads of individual nutrients (130, 322). intrajejunal infusion of glucose or saline distal to the occlu-
sion, 75 cm distal to the pylorus. Plasma GLP-1 levels in-
There may be sex-specific effects on GLP-1 secretion. Oral creased when glucose was infused intrajejunally in amounts
glucose and mixed-nutrient meals increased GLP-1 levels matching the aspirated glucose, but not when saline was
more in women than men in two studies (763, 805), but not infused intrajejunally. In the second (844), 2 kcal/min glu-
in two others (132, 385). In addition, oral glucose increased cose was infused either via intraduodenal catheters that
GLP-1 levels less during the follicular phase than during the ended 12 cm distal to the pylorus or via intrajejunal cathe-
luteal phase, apparently due to slower gastric emptying ters that ended 50 cm distal to the pylorus; in this condition
(101). a balloon was inflated 30 cm distal to the pylorus to exclude
reflux. Plasma GLP-1 levels increased markedly more when
Several mechanisms may contribute to the rapid initial glucose was infused intrajejunally than intraduodenally.
GLP-1 response: 1) GLP-1-cells are expressed in the duode- These two experiments demonstrate that small intestinal
num and proximal jejunum (148, 365, 738, 759), so direct glucose stimulation ⱖ50 –75 cm distal to the pylorus is
stimulation of GLP-1 secretion occurs as soon as ingesta necessary for GLP-1 secretion and that small intestinal glu-
pass the pylorus. 2) The initial rate of gastric emptying of cose stimulation ⬍50 – 60 cm distal to the pylorus is not
glucose solutions, especially in fasted subjects, may produce sufficient for it.
glucose concentrations that exceed the absorption capacity
of the proximal small intestine, so that glucose may reach Further observations also attest to the importance of distal
more distal GLP-1 cells within 5–10 min after meals (50, small intestinal GLP-1 cells in GLP-1 secretion. 1) Reducing
663). 3) The rate of increase in plasma GLP-1 may exceed intestinal nutrient transit with hyoscine decreased GLP-1
the rate of increase of plasma glucose, suggesting that neu- secretion in response to glucose (137). 2) GLP-1 secretion
roendocrine reflexes may stimulate GLP-1 secretion in ad- was increased when carbohydrates were administered with
dition to direct stimulation of GLP-1 cells by glucose (508). the acarbose, which slows digestion of starch and disaccha-
rides and increases the amounts of carbohydrates reaching
Intraduodenal-infusion studies, similar to oral-loading the more distal small intestine (274, 601, 680, 784, 785). 3)
studies, indicate that carbohydrate increases plasma GLP-1 GLP-1 secretion was increased more by lower glycemic load
levels faster than either protein or lipid (71, 247, 249, 412, foods, i.e., less digestible, than by higher glycemic load
446, 550, 583) and that biphasic responses sometimes oc- foods (635), again presumably by increasing the amounts of
cur (446, 583). In addition, 1) for each macronutrient, in- carbohydrates reaching the more distal small intestine. 4)
creasing caloric load increased GLP-1 levels (446, 583, Delivery of small amounts of lauric acid to the ileum and
640). 2) GLP-1 responses were greater during initially faster colon by enteric-coated pellets increased meal-induced
and subsequently slower nutrient infusions compared with GLP-1 secretion (459). 5) GLP-1 responses to intraduode-
identical loads infused at constant rates, suggesting that nal infusions of amino acids and fatty acids are slow in
increases in the initial intraluminal nutrient load dispropor- onset (71, 718), which, because no digestion is required in
tionally increase GLP-1 secretion (136, 550). Because gas- these situations, indicates that GLP-1 cells in the proximal
tric emptying rates are highest initially, this suggests that small intestine are not sufficient for the responses. 6) That

GLP-1 cells are more dense in the distal jejunum and ileum receptor FXR appears to inhibit GLP-1 production because
than in the more proximal small intestine in humans (233) treatment with a bile-acid sequestrant improved glucose
also supports the importance of the distal small intestine in tolerance and increased ileal GLP-1 expression in wild-type
GLP-1 secretion. mice, but not Fxr knockout mice (773). The importance of
bile acids for human GLP-1 secretion is not clear. 1) Bile
Many products of digestive hydrolysis directly stimulate acid and GLP-1 responses were correlated in one study
GLP-1 secretion via membrane receptors on the apical sur- (627). 2) Intrajejunal infusion of taurocholic acid did not
faces of enteroendocrine GLP-1 cells (TABLE 4, which in- affect GLP-1 secretion by itself, but increased glucose-stim-
cludes the full and the former names of the nutrient recep- ulated GLP-1 secretion beginning after ⬃90 min (841). 3)
tors discussed below). Intragastric infusion of lactisole, an Intraduodenal infusion of chenodeoxycholic acid had only
inhibitor of the TAS1R2/TAS1R3 sweet receptor, reduced a small effect on plasma GLP-1 levels (496).
the GLP-1 response to intragastric glucose in humans (275,
717), suggesting that GLP-1 cells express these receptors There appear to be several reflexive controls of GLP-1 se-
(228). TAS1R2/TAS1R3 receptors do not appear to be suf- cretion. 1) The nicotinic cholinergic antagonist trimeth-
ficient for GLP-1 secretion, however, because artificial aphan did not reduce the early increase in GLP-1 after a
sweeteners that stimulate them had no effect (716, 845, mixed-nutrient meal, but did reduce the increases in insulin
849). Glucose absorption via the glucose transporters and pancreatic polypeptide, suggesting that cephalic-phase
SLC5A1 and SLC2A2 may be required because selective reflexes did not contribute to the GLP-1 response (17). A
inhibitors of both transporters reduced GLP-1 secretion in preprandial cephalic-phase GLP-1 reflex, however, was
animals (461, 519). SLC2A1 and SLC2A5 have also been demonstrated in rats (180, 786). 2) The muscarinic cholin-
found on GLP-1 cells (618); the latter suggests a mechanism ergic antagonist atropine reduced the GLP-1 response to an
for the stimulation of GLP-1 secretion by fructose men- oral glucose load (50). 3) Mouse GLP-1 cells express the
tioned above. melanocortin 4 receptor (Mcr4), whose activation in-
creased GLP-1 secretion (561).
There is indirect evidence that protein hydrolysis is required
for GLP-1 secretion (142, 302, 322, 461, 718, 760). Oligo- The afferent limbs of GLP-1 reflexes may involve gastric-
peptides and amino acids may be sensed by CASR (210, phase signals because intragastric infusion of glucose or a
461). Phenylalanine, tryptophan, asparagine, arginine, and mixed-nutrient solution led to greater plasma GLP-1 levels
glutamine each stimulated GLP-1 in isolated rat small intes- than matched intraduodenal infusions (719), although it is
tine, and this was abolished in the absence of extracellular also possible that the initial rate of gastric emptying may
Ca2⫹ or the presence of a CASR inhibitor (461). have exceeded the rate of intraduodenal infusions, leading
to greater direct stimulation of GLP-1 release. An intestinal-
As for ghrelin and CCK, the effect of lipids on GLP-1 secre- phase reflex appears to contribute to GLP-1 secretion in
tion depends on digestive hydrolysis and the presence of response to intraduodenal fat infusions because GLP-1 did
fatty acids with chain length greater than or equal to C12 not increase after CCKAR antagonism (71). Finally, re-
(71, 249). The free fatty-acid receptors FFAR2, FFAR3, and search in rats indicates that vagal signaling contributes im-
FFAR4 are densely expressed on distal small intestinal portantly to reflexive GLP-1 release (29, 110, 628).
GLP-1 cells (329, 380, 715, 754), which may contribute to
the slower-onset, more sustained GLP-1 responses after
lipid ingestion. Carbohydrates reaching the large intestine C. Eating
are fermented to short-chain fatty acids, which are sensed
by FFAR2 and FFAR3 (206, 617) and contribute to the GLP-1 fulfills criterion 3 of TABLE 2 for an endocrine sati-
later phase of GLP-1 secretion (376, 765). For example, ation signal in humans because intravenous infusion of
oral loads of xylose, a poorly absorbed sugar, led to greater physiological doses of GLP-1 (0.3– 0.9 pmol·kg⫺1·min⫺1)
increases in GLP-1 than did glucose from 60 to 180 min reduced meal size in the absence of adverse effects in
after loading (793). GLP-1 cells also express GPR119, healthy-weight men (199, 255, 299, 301). Test context may
which mediates responses to oleoethylamine (151, 420, affect GLP-1 satiation, however, because a physiological
618), a long-chain fatty acid derivative formed during ab- dose failed to inhibit eating in another test (100), and sup-
sorption. raphysiological doses (1.2–1.5 pmol·kg⫺1·min⫺1 GLP-1)
reduced meal size in one (301), but not in another study
Nutrients may also stimulate GLP-1 secretion indirectly by done under different conditions (454). The site(s) of the
increasing bile secretion. Bile acids appear to control GLP-1 GLP-1R mediating this satiating effect is unknown. As ex-
secretion in two ways. First, circulating bile acids diffuse plained in section IVC, we conclude that positive results
into the lamina propria and reach GPBAR1 on the basolat- with physiological endocrine doses suggest that GLP-1 acts
eral aspects of GLP-1 cells, which stimulates GLP-1 secre- via an endocrine mode of action, rather than signaling lo-
tion in mice (105, 564, 761). Second, the nuclear bile-acid cally, to inhibit eating in these tests.

STEINERT ET AL.
With respect to criterion 6 of TABLE 2, GLP-1R antagonism Animal studies have also identified a number of brain sites
with exendin(9 –39) failed to increase test meal size in where GLP-1 may act to inhibit eating, including the area
healthy humans tested under five distinct experimental con- postrema, NTS, lateral parabrachial nucleus, ventral teg-
ditions (492, 721) and in two groups of RYGB patients mental area, paraventricular nucleus of the hypothalamus,
tested 3–12 mo after surgery, when their mean BMI was and nucleus accumbens (23, 219, 499, 500, 599, 619, 620,
⬃34 kg/m2 (737). In contrast, exendin(9 –39) did increase 652). Because the data reviewed above suggest that GLP-1
test meal size in one of the RYGB-patient groups in a pre- does not increase in the systemic circulation after meals in
operative test (737). Several factors may have contributed rats and that intestinal GLP-1 does not control eating in rats
to these disparate results. 1) The positive result was ob- via an endocrine mechanism, however, these sites are prob-
tained with a primed infusion and a higher maintenance ably physiologically stimulated by neuronal GLP-1 in rats,
dose of exendin(9 –39). 2) Meal-related GLP-1 secretion which originates in neurons in the caudal brain stem that
was markedly increased in the patients tested after RYGB, project to all the areas listed above and more (450, 623).
so even the higher exendin(9 –39) dose may not have been Because postprandial GLP-1 levels are relatively high in the
sufficient. 3) Patients were heavier before RYGB (⬃40 kg/ systemic circulation in humans, it is possible that endocrine
m2) than after (⬃34 kg/m2), suffered from T2DM, and were GLP-1 does affect these brain areas in humans. GLP-1 ap-
receiving insulin treatment (after RYGB only 2 of 12 pa- pears to enter the brain by simple diffusion (381). Finally,
tients had T2DM, and treatment was not specified). 4) Ex- rat studies indicate that GLP-1 signaling in the NTS affects
endin(9 –39) led to unusually high levels of PYY(3–36) in satiation in part by modulating the processing of signals
healthy subjects (721) and in patients tested after RYGB, related to gastric fill (312, 806), although whether endo-
but failed to increase PYY(3–36) in patients tested before crine or neurocrine GLP-1 is involved is unclear.
RYGB (737).
GLP-1 may contribute to postprandial satiety as well as to
Intravenous GLP-1 infusions failed to inhibit eating in men satiation. 1) As described above, GLP-1 levels are often
with truncal vagotomy and pyloroplasty (588), suggesting increased for several hours postprandially. 2) In a test of
that GLP-1 acts in the abdomen to inhibit eating. Many healthy-weight subjects who consumed fixed-size, high-fat,
data in rats also support a vagal mechanism (1, 313, 407, low-carbohydrate test meals (276), plasma GLP-1 levels
639), although capsaicin lesions of unmyelinated abdomi- 60 –180 min later were correlated with both hunger ratings
nal afferents failed to block GLP-1’s eating-inhibitory effect and the size of meals offered at 180 min (neither correlation
in one study (613). was present 0 – 60 min after the fixed-size meals). 3) In rats,
chronic intrajejunal infusions of linoleic acid increased
Additional rat and mouse data also indicate that intestinal GLP-1 levels and selectively reduced meal frequency, and
GLP-1 acts locally to inhibit eating in these species. 1) intraperitoneal exendin(9 –39) infusion reversed the reduc-
Meals failed to increase systemic active GLP-1 levels in rats tion in meal frequency (179).
(598, 691) [although meals did lead to GLP-1 increases in
mice (15, 297)]. 2) Infusion of 0.5 nmol/kg GLP-1 via the GLP-1 may affect eating in other ways. 1) GLP-1 may con-
cranial-mesenteric artery, which supplies much of the small tribute to flavor hedonics (24, 212, 499, 699, 827). Many of
and large intestines, reduced meal size more than identical the effects on rats’ eating produced by central GLP-1 ma-
infusions via the hepatic-portal vein or femoral artery in nipulations described above related to “hedonic eating,”
rats (832). 3) Hepatic-portal vein infusion of 1 nmol/kg and the effects of GLP-1 on human fMRI responses to pic-
GLP-1, which was near the threshold for an eating-inhibi- tures of foods also occurred in brain areas related to the
tory effect under the conditions tested in rats, increased generation of hedonic judgments (788). 2) GLP-1 signaling
active GLP-1 in portal-vein plasma to ⬃20-fold the maxi- in the caudal brain stem (624) and in the amygdala (388)
mum level observed after a meal under the same conditions may be involved in the aversive control of eating in rats. 3)
(599, 639). 4) Intraperitoneal injections of an GLP-1-albu- GLP-1 may have physiological roles in thirst and in sodium
min conjugate, which is unlikely to enter the brain, inhib- and water homeostasis (298, 485), which may influence
ited eating in mice (48). 5) In chow-fed rats, intravenous eating under some conditions. Future research should care-
infusions of GLP-1R antagonists failed to increase eating fully consider these possibilities.
(387, 638, 832), whereas intraperitoneal injections of
GLP-1R antagonists did so in several (37, 828, 831), al- There are two interesting distinctions between the eating-
though not all (3, 179, 832), tests. The inconsistent eating- inhibitory effects of chronic GLP-1 treatments in animals
stimulatory effect of intraperitoneal GLP-1-antagonist ad- versus in humans. 1) The site of action in humans is un-
ministration suggests that locally acting GLP-1 may be an known. Chronic GLP-1-agonist treatments that produce
endogenous satiation signal in rats only under particular weight loss in rats do so by acting centrally (379, 677, 698),
conditions. Dietary fat content may be one factor that whereas the long-lasting GLP-1 agonist liraglutide had low
downregulates the eating-inhibitory effect of GLP-1 (224, uptake into the cerebrospinal fluid in humans (150). 2)
595, 831). Visceral illness is not a serious side effect of GLP-1-agonist

treatment in humans (335, 414, 581), but reliably accom- cretin effect was diminished (47, 128, 223, 472). This ap-
panies the reductions in food intake and body weight pro- parently reflects a decrease in the ␤-cell response to GLP-1
duced by chronic GLP-1-agonist treatment in rats (379). and, more importantly, a near lack of response to GIP (332,
GLP-1 agonist-induced illness in rats is apparently medi- 392, 476, 491, 493, 538, 764, 842). As a result, GLP-1 may
ated by a subset of central GLP-1R sites (378). Better un- contribute relatively more to the incretin effect in T2DM
derstanding of these phenomena is important for advancing patients than in metabolically healthy persons (835). The
GLP-1 obesity pharmacotherapy. defect in the incretin effect in T2DM is reversible: improv-
ing glucose levels in patients with T2DM for only 4 wk
D. Glycemic Control improved C-peptide secretion in response to both GLP-1
and GIP infusions markedly (332). Thus GLP-1 agonists
GLP-1 appears to contribute to meal-related glycemic con- hold great promise for the treatment of T2DM. GLP-1-
trol by stimulating insulin secretion, inhibiting glucagon based therapy, however, may not be advantageous for all
secretion, slowing gastric emptying, and reducing hepatic T2DM patients. For example, the discovery of gene poly-
glucose metabolism (128, 222, 336, 653). GLP-1 may also morphisms that affect incretin hormone secretion and ac-
contribute to glycemic control in the fasting state. The latter tion in T2DM patients (527) and that affect GLP-1’s insuli-
is suggested by recent studies employing pancreatic clamps, notropic effect in healthy individuals (657) suggest that de-
i.e., somatostatin infusion and glucagon and insulin re- fects in incretin function may be a primary pathophysiology
placement, that suggest that GLP-1 reduces endogenous in some patients.
glucose production during the fasting state in both metabol-
ically healthy individuals (594) and those with T2DM GLP-1’s glucagonostatic action also contributes to meal-
(679). Studies in mice suggest that these effects are due in
related glycemic control. Physiological infusions of 0.25–
part to an insulin-independent effect GLP-1R in the hepatic
0.4 pmol·kg⫺1·min⫺1 GLP-1 inhibited glucagon secretion
portal vein or liver (117).
and reduced glucose levels in both healthy subjects and
T2DM patients (309, 352), and exendin(9 –39) markedly
GLP-1, together with GIP, mediates the incretin effect by
elevated glucagon secretion and increased glucose levels in
exerting dose-related, glucose-dependent insulinotropic ef-
healthy subjects (230, 546, 721).
fects on ␤-cells (128, 223, 336, 406). Infusions of physio-
logical endocrine doses of GLP-1 are sufficient to increase
As described in section IIC, GLP-1 slows gastric emptying,
insulin secretion in fasting subjects and during glucose in-
which also improves glycemic control (448, 541, 659, 834).
fusions (406, 537, 803). Furthermore, a physiological dose
Comparisons of the relative contributions of GLP-1’s di-
of GLP-1 infused during isoglycemic glucose infusions, i.e.,
infusions leading to identical glycemic profiles as oral glu- verse effects on glycemia suggest that its glucagonostatic
cose, reproduced the insulin response to oral glucose (537). and gastric-emptying inhibitory effects are more important
These data indicate that GLP-1 meets criterion 3 of TABLE 2 than its insulinotropic effect in healthy subjects (541, 546).
for a physiological endocrine incretin effect. Infusion of the Several aspects of GLP-1’s effect on GI motility are relevant
GLP-1R antagonist exendin(9 –39) decreased insulin secre- for the treatment of T2DM. 1) The slowing of gastric emp-
tion after oral glucose loads, after meals, during intraduo- tying by exogenous GLP-1 displayed tachyphylaxis during
denal glucose infusions, and during hyperglycemic glucose sustained (⬎24 h) GLP-1 infusions in healthy subjects (540,
clamps (546, 650, 664, 721), indicating that GLP-1 meets 781). 2) Shorter-acting GLP-1 agonists have a more sus-
also criterion 6 for a physiological endocrine incretin effect. tained effect on gastric emptying and thereby reduce meal-
related glycemia more than longer-acting GLP-1 agonists
Additional important aspects of the incretin effect in meta- (577). 3) A short-acting GLP-1 agonist also reduced duode-
bolically healthy individuals include 1) comparisons of in- nal motility and flow, suggesting an additional mechanism
sulin or C-peptide secretion in response to oral glucose or by which GLP-1 may reduce meal-related glycemia (756).
isoglycemic intravenous glucose infusions indicate that the
incretin effect increases with increasing glucose loads and, Additional mechanisms also may contribute to GLP-1’s gly-
thus, limits meal-related glucose excursions even after large cemic effects. A study in truncally vagotomized human sub-
glucose loads (47, 490, 539). 2) GLP-1 synergizes with GIP jects indicated that the vagus is involved in GLP-1’s effect
to increase insulin secretion (537, 803), but 3) intraduode- on GI glucose disposal, but not in its incretin effect, al-
nal glucose infusions at rates in the physiological range of though a limitation was that the subjects had pyloroplasty
gastric emptying of glucose solutions indicated that GIP together with vagotomy (587). This effect of GLP-1 on
was the predominant incretin during infusion of ⱕ2 kcal/ glucose disposal may involve GLP-1R in the hepatic-portal
min glucose, whereas GLP-1 predominated during infusion vein, which animal studies indicate activate neural reflexes
of either 3 or 4 kcal/min glucose (471, 774). that increase glucose clearance without affecting insulin se-
cretion (117, 355, 548). The role of these reflexes in normal
Although glucose stimulated GLP-1 and GIP secretion nor- meal-related glucose control remains unclear. Mice with
mally in patients with T2DM (47, 121, 460, 542), the in- global deletion of GLP-1R in which GLP-1R were selec-

STEINERT ET AL.
tively reconstituted in the pancreas displayed normal oral F. RYGB

and intraperitoneal glucose tolerance (417), suggesting
the endocrine mechanism is sufficient and neural and Meal-related GLP-1 secretion is substantially increased af-
other mechanisms are not necessary. Other data suggest ter RYGB (94, 310, 574, 846). Although fasting GLP-1
that brain GLP-1R also may contribute GLP-1’s glycemic levels are usually unchanged, meal-related GLP-1 increases
effects: 1) GLP-1 infusions into the third cerebral ventri- within 2 days of surgery, increases progressively for at least
cle increased insulin secretion in rats and mice (393, 652) 6 mo, and persists apparently indefinitely. As described in
and decreased gastric-emptying rates in rats (354); 2) section IIG, increased gastric empting may account for
exendin(9 –39) infusions into the third cerebral ventricle these increases in GLP-1 secretion when highly digestible
nutrients enter the Roux limb rapidly, as in the case of oral
increased muscle glucose utilization independent of insu-
glucose challenges (544). Increases in meal-related GLP-1
lin signaling in mice (393); and 3) GLP-1 infusions di-
secretion may contribute to the beneficial effects of RYGB
rectly into the Arc reduced hepatic glucose production in
on eating, body weight, and glycemic regulation: 1) the
rats (652). Whether these central effects reflect actions of
magnitude of meal-related GLP-1 responses has been asso-
enteroendocrine GLP-1 or neural GLP-1, however, is un-
ciated with weight loss (214, 425) and remission of T2DM
clear. (533); and 2) patients bearing the MC4R variant I251L lost
more weight after RYGB (502), which may reflect increased
GLP-1 secretion (469).
E. Obesity
Tests of acute somatostatin treatment support the involve-
The peak and AUC of meal-stimulated GLP-1 secretion ment of GLP-1 and PYY(3–36) on RYGB’s eating effects. 1)
were reduced in several studies of obese persons (6, 130, Somatostatin treatment decreased meal-related GLP-1 and
458, 497, 603, 798), although not all (245, 681, 794). PYY(3–36) levels, decreased fullness rating during a test
These decreases appear to be secondary to obesity because meal, and increased test-meal size in RYGB patients; it was
meal-stimulated GLP-1 secretion increased to near that of not established that these effects were specific to RYGB,
healthy-weight individuals in obese patients following however, as no unoperated control subjects were tested
weight loss (from mean BMI of 39 to 33 kg/m2) achieved by (191, 425). 2) Somatostatin failed to affect pre-meal hunger
caloric restriction (798). Obesity does not appear to influ- ratings but did increase progressive-ratio responding for
ence GLP-1’s incretin effect because the ␤-cell response to chocolate sweets in RYGB patients more than it did in con-
GLP-1 infusion during hyperglycemic clamps increased in trol subjects, an effect the authors interpreted in terms of
proportion to insulin resistance in individuals without hedonics rather that satiation (283). 3) In a rat study, so-
T2DM identically in healthy-weight and morbidly obese matostatin injection appeared to increase eating more in
subjects (42). Postprandial circulating bile-acid levels are RYGB than in control animals, although the difference was
reduced in obesity (570), which may contribute to the re- not tested statistically (251). In view of the myriad effects of
duction in GLP-1 secretion. somatostatin, whether these effects were due to changes in
GLP-1, PYY(3–36), or other effects is uncertain. Similarly,
A polymorphism in GLP1R at rs2268641 was associated simultaneous antagonism of GLP-1R with exendin(9 –39)
with BMI in a European-American sample, although it ac- and inhibition of PYY(3–36) synthesis with sitagliptin
counted for ⬍0.3% of the variance (430), suggesting that (Januvia or Sitagliptin, Merck, Kenilworth, NJ) increased
test meal size ⬃20% in RYGB patients, although neither
defects in GLP-1 signaling contribute to obesity risk in some
treatment alone affected test meal size (737). These data
individuals. Tests of GLP-1’s effects on eating in children
suggest that GLP-1 and PYY(3–36) have a synergistic sati-
who are at high familial risk for obesity before they become
ating action after RYGB. Again, however, it was not estab-
hyperphagic and overweight (see Ref. 726) would be useful
lished that the effect of the combination treatment was in-
in analyzing this. creased by RYGB because no unoperated control subjects
were tested.
Intravenous infusion of physiological doses of GLP-1 inhib-
ited eating in obese subjects in three studies (256, 300, 534) Studies of the role of GLP-1 in RYGB in rodents produced
and failed to do so in one, apparently underpowered study mainly negative results. 1) In RYGB rats, acute administra-
(535). Although these studies did not include nonobese con- tion of exendin(9 –39) increased eating in one test (3), but
trol groups, an across-study analysis of 72 normal-weight not in two others (37, 477). 2) The GLP-1R agonist exen-
and 43 overweight and obese subjects, some with T2DM, din-4 had comparable effects in RYGB and sham-operated
failed to detect any change in the dose-effect relations of rats (251). 3) Meals increased systemic GLP-1 levels in
infusions of 0.4 –1.5 pmol·kg⫺1·min⫺1 GLP-1 (796). As de- RYGB rats (691), suggesting that brain GLP-1R may medi-
scribed in section VC, exendin(9 –39) increased test meal ate RYGB’s eating-inhibitory effect. But chronic infusions
size in morbidly obese patients with T2DM, but no longer of exendin(9 –39) into the lateral cerebral ventricle in-
did so after RYGB (737). creased food intake and weight gain similarly in RYGB and

sham-operated rats, suggesting that central GLP-1R are maturation. In any case, these data provide an important
not involved in the effects of RYGB (848). Unfortunately, challenge to the human literature.
the effects of peripheral GLP-1 were not assessed, so it
was possible that peripheral GLP-1 signaling contributed RYGB increases meal-stimulated circulating bile-acid levels
to the observed effects of RYGB. 4) RYGB had compa- (157, 570, 740), which might contribute to RYGB-induced
rable weight-loss and eating-inhibitory effects in mice increases in GLP-1 secretion and to RYGB’s therapeutic
with transgenic deletions of GLP-1R (Glp1r⫺/⫺) or effects. Consistent with this hypothesis, meal-stimulated
Gnat3 (␣-Gust⫺/⫺), which do not secrete GLP-1 in re- bile-acid and GLP-1 responses were associated in several
sponse to oral glucose, and wild-type mice (507, 848). studies done 4 mo or more after RYGB (396, 566, 668,
Thus the preponderance of evidence from animal models 820). But meal-stimulated bile-acid levels did not increase
argues strongly against the hypothesis that GLP-1 con- in tests 1 wk, 1 mo, or 3 mo after RYGB (16, 720). Thus,
tributes importantly to the eating-inhibitory and weight- because meal-related GLP-1 levels are markedly increased
loss effects of RYGB (the Glp1r⫺/⫺ and ␣-Gust⫺/⫺ mod- at these times, any contribution of elevated bile-acid levels
els are discussed further below). to GLP-1 secretion or the effects of RYGB are likely to be
late-developing mechanisms. Finally, mouse models sup-
In marked contrast to the eating data, there is compelling port the hypothesis that changes in bile acids contribute to
evidence that GLP-1 contributes in several ways to the ben- the effects of bariatric surgery. 1) Diversion of bile to the
eficial effects of RYGB on glycemic regulation in humans. ileum increased circulating bile acids 10-fold and led to
The clearest evidence is that exendin(9 –39) markedly re- decreases in food intake, glycemia, and body weight that
duced insulinemia and increased glycemia after consump- were similar to those produced by RYGB and appeared to
tion of mixed-nutrient meals or glucose solutions tested 1 be at least in part independent of fat malabsorption; unfor-
wk to 5 yr after RYGB (371, 375, 648 – 650, 684, 736). This tunately, the role of GLP-1 was not assessed (257). 2) A
also occurred in RYGB patients with T2DM (371, 375). transgenic mouse-model study (642) implicated FXR in the
Additionally, exendin(9 –39) increased glucagon secretion efficacy of vertical-sleeve gastrectomy; again, the impor-
(375, 650, 736) and accelerated gastric emptying rate in one tance of GLP-1 was not assessed. Furthermore, although
vertical-sleeve gastrectomy increased circulating bile acids
study (684), although not another (650). In contrast to
in mice (529), the human data are mixed (157).
these increased effects of GLP-1, RYGB did not appear to
increase the contribution of GIP to meal-related glycemic
control (736). A dual-isotope glucose-tracing study indi- G. Summary
cated that GLP-1 was not involved in the reduction of en-
dogenous glucose production and the increase in glucose GLP-1 is secreted in response to the products of carbohy-
disposal after RYGB (375). Increased GLP-1 secretion after drate, lipid, and protein digestion. It may act as an endo-
RYGB also contributed to the development of meal-related crine satiation signal in healthy humans, but antagonist
hyperinsulinemic hypoglycemia in some patients (647– 649; studies have not yet confirmed this. Intestinal and brain
for reviews of these and related data, see Refs. 468, 646, GLP-1 also may have other effects on ingestive behavior,
653). It is also important to note that reduced eating also but these are not established in humans. Intestinal GLP-1
contributes importantly to the improvements in glycemic reduces meal-related increases in glycemia by stimulating
control after RYGB (361, 363, 415). insulin secretion (i.e., acting as an incretin), by inhibiting
glucagon secretion, by slowing gastric emptying, and, per-
Exendin(9 –39) treatment also reversed the improvements haps, other effects. The effects of GLP-1 on eating and
in glucose tolerance and insulin secretion after RYGB in a glycemic control are summarized in FIGURE 10. Defects in
rat model (138). There is a disconnect, however, between GLP-1 secretion or signaling may contribute to overeating
the demonstrations with exendin(9 –39) of the importance in obesity. Although GLP-1’s effectiveness in glycemic con-
of GLP-1 for glycemic regulation after RYGB and a report trol decreases in individuals with insulin resistance or
(507) that Glp1r⫺/⫺ and ␣-Gust⫺/⫺ mice with RYGB and T2DM, it remains a crucial contributor, and GLP-1 ago-
wild-type RYGB mice had similar glucose tolerance, insulin nists are already in use in T2DM and obesity therapy.
tolerance, and glucose-stimulated insulin release [␣- GLP-1 contributes to improved glycemic control after
Gust⫺/⫺ mice, which do not secrete measureable GLP-1, RYGB; its role in eating after RYGB is unclear.
were used to test the role of GLP-1’s degradation products
GLP-1(9 –36)amide and GLP-1(28 –36)amide, which may
VI. PYY(3–36)
improve glucose homeostasis via GLP-1R-independent
mechanisms]. The resolution of this apparent paradox is
unclear. It is possible that there are important species dif- A. Introduction
ferences. In addition, because these were germline trans-
genic animals, mechanisms compensating for the lack of Endocrine PYY is synthesized and secreted by open-type
GLP-1 signaling may have developed during the animals’ enteroendocrine cells (FIGURE 6B). Enteroendocrine PYY

STEINERT ET AL.
PYY is also expressed in the endocrine pancreas, where

GLP-1 1 Satiation
PYY(1–36) may have paracrine intraislet actions (573). Fi-
nally, PYY is expressed by neurons in the gigantocellular
reticular nucleus of the rostral medulla, which have wide-
spread central projections (280).
PYY(1–36) activates several neuropeptide Y-family recep-

tors, including NPY1R (or Y1R), NPY2R, NPY4R, and
NPY5R, whereas PYY(3–36) is selective for NPY2R (120,
226, 697, 807). NPY2R are expressed throughout the body,
including in several brain regions, the GI tract, and vagal
2 Meal-related
glycemia afferents.
β α
Digested
nutrients
B. Secretion
Difficulties in assaying PYY(3–36) complicate studies of its

physiology (467, 768, 769). Therefore, the plasma levels
described here refer to total PYY. Plasma PYY levels gen-
3 Gastric emptying erally begin to increase ⬃15–30 min after meals, reach max-
ima ⬃60 –90 min after meals, and remain elevated for sev-
eral hours so that morning fasting levels are not reached
until several hours after evening meals (51, 61, 64, 198,
241, 276, 326, 453, 713). Morning fasting PYY levels are
typically 10 –20 pM, and peak levels after moderate-size
meals are ⬃15–30 pM (10, 198, 276). Postprandial PYY
and GLP-1 profiles are often dissimilar because DPP-4 ac-
FIGURE 10. Some features of GLP-1 physiology. GLP-1 secretion
tivates PYY, but inactivates GLP-1 (233, 520), and because,
is stimulated by the digestive products of all three macronutrients at least in rodents, the enteroendocrine cells that express
acting on nutrient receptors on the apical aspects of enteroendo- PYY are located more distally than those that express
crine GLP-1 cells (blue) dispersed in the epithelial layer (tan) of the GLP-1 (597, 738).
small intestinal mucosa. GLP-1 acts in an endocrine mode by diffus-
ing through the lamina propria (yellow) and into intestinal capillaries
(salmon) to reach distant target organs (red arrows), or acts locally.
Orally ingested lipids lead to larger and more sustained
1) GLP-1 stimulates satiation. Data in rats indicate GLP-1 signals elevations in plasma PYY than glucose ingestion (10, 103,
satiation via a local action on vagal afferents (green arrow) in the 241, 276, 319, 462); the relative effect of protein is less clear
lamina propria. GLP-1 may also act in the brain to affect satiation or (10, 64, 317, 319, 787). The PYY effects in these studies
postprandial satiety. 2) GLP-1 improves meal-related glycemia by were relatively variable, possibly reflecting assay variabil-
increasing pancreatic ␤-cell insulin secretion in a glucose-dependent
manner, by inhibiting pancreatic ␣-cell glucagon secretion, and by
ity, differences in gastric emptying, time of day (317), test-
inhibiting gastric emptying; all three appear to be endocrine effects food digestibility, or subject variables, including differences
of GLP-1. 3) GLP-1 slows gastric emptying via a direct endocrine in DPP-4 activity (467).
effect and perhaps via a vagal-vagal reflex. Solid lines indicate well
established effects, and dashed lines indicate less well established Lipid-induced PYY secretion is dependent on hydrolysis
effects.
and fatty-acid chain length greater than or equal to C12
(197, 250). Amino acids stimulated PYY release (718), but
cells are located predominately in the distal small intestine whether PYY release requires protein hydrolysis has not
and colon and often coexpress and secrete GLP-1 and, less been assessed directly. Acarbose increased PYY levels after
frequently, CCK, GIP, neurotensin, or secretin (8, 10, 25, a mixed-nutrient meal (265), suggesting that secretion is
231, 303, 597, 738, 742). Plasma PYY is a mix of PYY(1– increased when carbohydrates reach the distal small intes-
36), the secreted form, PYY(3–36), the active endocrine tine or proximal colon, where the densities of PYY cells are
form, which results from cleavage of the tyrosine-proline higher. This suggestion is consistent with the increased PYY
residue from the NH2-terminal of PYY(1–36) by DPP-4 in levels in patients with dumping syndrome, tropical sprue,
the lamina propria (296, 451), capillary endothelial cells, small-intestinal resection, or RYGB (12–14, 467, 574).
liver and blood (51, 289, 488), and some breakdown frag-
ments (768, 769). As discussed in section IB2, mouse intes- The stimulation of enteroendocrine PYY secretion via
tinal PYY cells appear to release some PYY from axon-like membrane nutrient receptors has been less extensively stud-
cytoplasmic extensions, or neuropods, that end in close ap- ied than for ghrelin, CCK, and GLP-1 (TABLE 4, which
position to glial cells of the enteric nervous system (92, 93). includes the full and the former names of the nutrient re-

ceptors discussed below). Carbohydrate (glucose in most PYY to ⬃45– 60 pM, more than the ⬃40 pM produced by
studies) appears to stimulate PYY secretion in part via stim- a 3000 kcal meal in the same study (423). 3) Infusion of
ulation of TAS1R1/TAS1R3 sweet receptors (228, 275, lower PYY(3–36) doses, 0.2– 0.3 pmol·kg⫺1·min⫺1, failed
717), but because equally sweet artificial sweeteners did not to affect subsequent meal size (194, 701). Thus doses of
trigger PYY release, other mechanisms must be also in- PYY(3–36) that inhibited eating in these studies increased
volved (461, 716, 732, 849). Whether FFAR1 or FFAR4 plasma PYY levels more than all but extremely large meals,
contributes to PYY secretion has not been studied to our suggesting that the effects of PYY(3–36) on postprandial
knowledge, but given that many enteroendocrine cells pro- satiety do not meet criterion 3 of TABLE 2 for a physiological
duce both GLP-1 and PYY (304), it is likely that they do so. endocrine dose. This conclusion is consistent with the re-
CASR appears to contribute to the stimulation of PYY se- port (276) that the 3 h total PYY AUC after high-carbohy-
cretion by oligopeptides and amino acids because their ef- drate, low-fat breakfasts or low-carbohydrate, high-fat
fects on PYY secretion in isolated loops of rat small intes- breakfasts were not significantly correlated with the sizes of
tine were reduced by a CASR inhibitor and dependent on the following lunches, even though ghrelin and GLP-1 AUC
extracellular Ca2⫹ (461). after each breakfast were significantly correlated with lunch
sizes. In addition, although adverse effects were not re-
Neurohumoral reflexes also appear to contribute to PYY ported when 0.8 pmol·kg⫺1·min⫺1 PYY(3–36) was infused
release, especially its early phase (51, 227, 586). 1) Intrave- following standard meals (62, 194, 423), when infused in
nous CCK infusions increased plasma PYY in humans fasting subjects, this dose elicited “severe malaise or nau-
(102). 2) GLP-1 infusion decreased (104) and exendin(9 – sea” in half the subjects in two studies (701, 768). These
39) infusion increased (230, 721) PYY secretion, perhaps data suggest that criterion 5 of TABLE 2, that the effect of
reflecting an autoregulatory mechanism in GLP-1/PYY PYY(3–36) on satiety effect be selective, requires further
cells. 3) Bile acids may be an important mediator, particu- testing. In addition, in all these studies the test meals were
larly of lipid-stimulated PYY secretion (9, 11, 569, 840). 4) offered at fixed times; thus future tests in which subjects are
Animal studies implicated vasoactive intestinal polypeptide asked to report when they wish to initiate meals may reveal
and the vagus nerve in PYY secretion (9, 51–53, 264, 685).
effects of PYY(3–36) on the duration of the intermeal inter-
5) Some mouse PYY cells express Mc4r, which appears to
val, which is hypothesized to be under the control of post-
facilitate PYY secretion (561).
prandial satiety processes (see sect. IB1).
C. Eating Only one study of the satiating effect of intrameal PYY(3–

36) infusions has been reported (198). This revealed 1) the
The eating-inhibitory effect of peripheral PYY is mediated threshold dose for a significant reduction in meal size was
by PYY(3–36) (62, 144, 172, 676). 1) Intravenous infusion between 0.2 and 0.4 pmol·kg⫺1·min⫺1 PYY(3–36); 2) infu-
of PYY(3–36) inhibited eating ⬃10-fold more potently than sion of 0.2 and 0.4 pmol·kg⫺1·min⫺1 PYY(3–36) increased
infusions of PYY(1–36) in rats and, comparing across ex- plasma total PYY from the fasting level of ⬃10 to ⬃25 and
periments, ⬃4- to 8-fold more potently in humans (69, 198, ⬃31 pM, respectively, which was more than the level of
701). 2) Central administration of PYY(1–36) stimulated ⬃13 pM achieved after a 1500 kcal mixed-nutrient meal;
eating in rats. and 3) 0.4 pmol·kg⫺1·min⫺1 PYY(3–36) often led to nau-
sea. These data suggest that the eating-inhibitory effects of
Potential roles of PYY(3–36) in both satiation and post- intra-meal PYY(3–36) infusions in this experiment were
prandial satiety have been investigated. Four studies (62, pharmacological, rather than physiological, and were due
194, 423, 701) modeled PYY(3–36)’s postprandial satiety in part to aversive effects, i.e., they failed to meet criteria 3
effect using intermeal infusions that began after standard and 5 of TABLE 2. Furthermore, because only slightly sup-
meals (62, 194, 423, 701) or after an overnight fast (701) raphysiological intravenous doses of PYY(3–36) elicited ill-
and ended before the test meal. 1) In one test, infusion of a ness and because such doses presumably elicit infraphysi-
supraphysiological dose of 0.8 pmol·kg⫺1·min⫺1 PYY(3– ological paracrine levels of PYY(3–36) in the lamina pro-
36) for 90 min increased peak plasma PYY(3–36) concen- pria, it is difficult to see how PYY(3–36) could have a
tration from ⬃8 to ⬃44 pM and reduced the size of a buffet physiological paracrine action on eating. Perhaps, however,
meal presented 2 h after the infusion ended (62). The au- current methods either fail to mimic a crucial aspect of
thors concluded that this was a physiological effect because endogenous PYY(3–36) dynamics or fail to provide some
in a previous study, meals of 530, 870, and 4500 kcal in- aspect of normal meals that prevents endogenous PYY(3–
creased PYY to from ⬃8 –10 pM to ⬃12, ⬃25, and ⬃55 36) from provoking illness.
pM, respectively (10). 2) In another test, the threshold for a
significant decrease in meal size was 0.7 pmol·kg⫺1·min⫺1 Studies in animals do not strongly support a physiological
PYY(3–36), although infusion of 0.5 and 0.6 pmol· role for PYY(3–36) in eating. Intramuscular injections of
kg⫺1·min⫺1 PYY(3–36) increased fullness and tended to PYY(3–36) reduced eating in monkeys, but how the doses
decrease eating. These infusions increased peak plasma administered compared with endogenous levels was unclear

STEINERT ET AL.
(517). In one study, hepatic-portal infusions of PYY(3–36) more, as described in section IB2, some PYY is apparently
inhibited eating in rats without signs of illness (710), but released from neuropods (92, 93), and analysis of the po-
systemic intravenous infusions of PYY(3–36) that inhibited tential effects of this is beyond available physiological meth-
eating in rats did produce illness (143, 144), as did intra- ods. Finally, Batterham and colleagues (64, 467) hypothe-
peritoneal injections of PYY(3–36) in mice (306). Interest- sized that PYY is involved in protein-induced satiety and in
ingly, however, intravenous infusions of a peripherally act- exercise-induced anorexia, which have not been extensively
ing NPY2R antagonist reduced the eating-inhibitory effects tested, and in food reward, which has been tested in a num-
of intravenous infusions of PYY(3–36) and of smaller, but ber of human functional brain imaging studies that we do
not larger, intragastric loads of protein and fat in rats (614), not review (63, 194, 818).
suggesting that PYY(3–36) fulfills criterion 6 of TABLE 2
under some conditions. Infusion of the NPY2R antagonist
by itself failed to increase eating, however, which fails to
D. Glycemic Control
provide support for criterion 6 of TABLE 2. Studies of mice
with transgenic deletions of Pyy also provide only weak There is little evidence that PYY(3–36) affects insulin secre-
support for a role in eating (441). In one Pyy⫺/⫺ mouse line, tion in humans. Infusion of 1 or 5 pmol·kg⫺1·min⫺1
male mice were hyperphagic and females were not tested PYY(3–36) failed to affect the insulin response to a bolus
(64); in another, females but not males were hyperphagic intravenous glucose infusion in fasting women (19), and
(88); and in two others no eating phenotype was detected PYY(3–36) infusions during meals failed to increase plasma
(669, 838). Ectopic Pyy overexpression in adult mice failed insulin levels (61, 62), except when the doses elicited illness
(701, 834).
to affect body weight, but slightly decreased eating after a
24 h fast (686). As none of these transgenic methods dis-
In contrast, animal studies suggest that PYY affects glycemic
criminated between effects of PYY(1–36) and PYY(3–36),
regulation in two apparently opposing ways. 1) PYY(3–36)
it is possible that more refined molecular genetic tools will
may indirectly stimulate nutrient-induced insulin secretion in
provide more useful information. Finally, although knock-
rodents. PYY(3–36) reduced postprandial glycemia without
out of peripheral NPY2R in mice increased eating under
affecting fasting glycemia, an effect mimicked by a NPY2R
some conditions, it appeared that this was secondary to
agonist, and this was blocked by peripheral, but not central,
metabolic effects (687, 851).
administration of a NPY2R antagonist (140, 467). This effect
of PYY(3–36) appeared to be mediated by GLP-1 because
Whether PYY(3–36) acts peripherally or centrally to inhibit
exendin(9 –39) blocked the glucose-lowering effects of
eating is unclear. In support of peripheral action, 1) subdi-
PYY(3–36) (140, 467). 2) PYY(1–36) may directly inhibit in-
aphragmatic vagotomy reduced or abolished the eating- sulin secretion via a paracrine mode of action. In mice, PYY is
inhibitory effect of peripherally administered PYY(3–36) in expressed in pancreatic ␣- and ␦-cells, Npy1r and Npy4r, but
rats (56, 395), 2) conjugating PYY(3–36) to albumin to not Npy2r, are expressed in ␤-cells, and PYY(1–36), but not
prevent it from crossing the blood-brain barrier reduced its PYY(3–36), dose-dependently reduced glucose-stimulated in-
eating-inhibitory potency (56), and 3) an NPY2R antago- sulin release from ␤-cells in vitro (116, 140, 467, 573, 651,
nist that does not cross the blood-brain barrier blocked 790). Furthermore, this was absent in cells derived from
the eating-inhibitory effect of peripherally administered Pyy⫺⫺/⫺ or Npy1r⫺/⫺ mice, and both mutants were hyperin-
PYY(3–36) (614). In support of central action, 1) injections sulinemic (88, 116).
of PYY(3–36) directly into the Arc reduced eating in rats
(2), 2) injections of an NPY2R antagonist into the Arc re- PYY may contribute to glycemic regulation via two further
duced the eating-inhibitory effect of peripherally adminis- actions. 1) Endocrine intestinal PYY(3–36) may improve in-
tered PYY(3–36) in rats (2), 3) PYY(3–36) inhibited eating sulin sensitivity, at least under some conditions, because intra-
in vagotomized mice (306), and 4) PYY(3–36) inhibited venous infusion of PYY(3–36) increased glucose uptake in
eating in rats with capsaicin lesions of unmyelinated ab- muscle and adipose tissue of high-fat fed mice during a hyper-
dominal afferents (613). insulinemic-euglycemic clamp (790). 2) Paracrine pancreatic
PYY(1–36) may tonically stimulate islet-cell proliferation and
In conclusion, present data fail to support the hypothesis inhibit ␤-cell apoptosis in mice (573, 651). 3) Any decrease in
that PYY(3–36) physiologically inhibits eating in humans gastric emptying produced by PYY(3–36) may lead to reduc-
or animals. Further efforts to determine whether PYY(3– tions in glycemia.
36) infusions that better model the dynamics of human and
animal PYY secretion around meals have physiological eat- Interestingly, oral fat loads and mixed-nutrient meals ap-
ing-inhibitory effects are required to determine whether pear to stimulate less PYY secretion in patients with T2DM
PYY(3–36) is a plausible candidate physiological satiation (238, 252, 856). To investigate whether this precedes
or postprandial satiety signal. Studies of antagonism of T2DM, Viardot et al. (801) compared subjects with strong
PYY(3–36)-NPY2R signaling are also necessary, but spe- family histories of T2DM with subjects matched for insulin
cific antagonists for human use are not available. Further- sensitivity, age, and BMI, but without family histories of

T2DM. PYY responses to high-carbohydrate meals were different if tested when RYGB reduced eating. 2) Pyy⫺/⫺
impaired in the subjects at risk for T2DM, suggesting that mice lost less weight than wild-type mice during the initial
defective PYY secretion may be causally linked with 10 days after surgical bypass of the duodenum and proxi-
T2DM. mal jejunum; unfortunately, food intakes were not reported
(141). Finally, as noted in section VIF, increases in PYY(3–
36) secretion in patients bearing the MC4R variant I251L
E. Obesity (469) could explain their better weight-loss outcomes after
RYGB (502).
The relationship between obesity and PYY secretion is un-
clear. 1) Although several studies detected decreases in fast-
ing total PYY levels in obese patients (61, 64, 423, 633, G. Summary
856), other similarly powered studies did not (333, 385,
576, 727, 794). 2) Weight reduction was reported to in- PYY(3–36) is secreted in response to the products of carbo-
crease fasting total PYY in obese children (633), but to hydrate, lipid, and protein digestion during and after meals.
decrease it in obese adults (576), although in both studies As summarized in FIGURE 11, PYY(3–36) may contribute to
the weight and PYY changes were small. 3) Postprandial
PYY secretion was reduced in obese patients in six studies
(61, 64, 422, 423, 497, 727, 856), but not in four others PYY(3-36) 1 Satiation
(103, 333, 385, 794). 4) In the one comparison of PYY(3–
36)’s eating-inhibitory effect in obese and healthy-weight
subjects to date, no difference was detected (61).
F. RYGB
There are several reports that postprandial plasma PYY

levels increase at various times after RYGB, with little or no
change in fasting levels (39, 213, 310, 425, 846). As yet,
however, there is a dearth of knowledge concerning the time 2 Meal-related
glycemia
courses or physiological consequences of these increases.
For example, in one study (94), 3 h AUC of PYY after a 420 Digested
nutrients
kcal mixed-nutrient meal was not significantly increased ?
until 3 mo after RYGB, whereas in another (574), both
maximum postprandial PYY levels and 3 h PYY AUC after
424 kcal mixed-nutrient meals were increased more 1 wk
postoperatively than 3 or 12 mo postoperatively.
3 Gastric emptying
We know of only one test of the eating-inhibitory effect of

PYY(3–36) in RYGB patients, in which inhibition of PYY(3–
36) synthesis with sitagliptin failed to increase test meal size
(737). But somatostatin treatment (191, 425) and simultane-
ous exendin(9 –39) and sitagliptin treatment (737) both in-
creased test meal size in RYGB patients, suggesting that GLP-1
and PYY(3–36) synergize to decrease eating after RYGB (these
FIGURE 11. Some features of PYY(3–36) physiology. PYY secretion
data were reviewed in sect. VF). Because neither test included is stimulated by the digestive products of all three macronutrients
unoperated control subjects, whether RYGB increased the ef- acting on nutrient receptors on the apical aspects of enteroendocrine
fects is uncertain. PYY cells (blue) dispersed in the epithelial layer (tan) of the small-
intestinal mucosa. PYY is transformed into PYY(3–36) beginning in the
Two additional rodent studies of PYY(3–36)’s involvement lamina propria. PYY(3–36) acts in an endocrine mode by diffusing
through the lamina propria (yellow) and into intestinal capillaries
in RYGB produced mixed results: 1) chronic infusions of a (salmon) to reach distant target organs (red arrows), or acts locally. 1)
NPY2R antagonist into the lateral cerebral ventricle failed The role of PYY(3–36) in eating is uncertain. It may inhibit eating via a
to affect food intake or weight gain in either RYGB or local action on vagal afferents (green arrow) in the lamina propria or by
sham-operated rats (848). Although this fails to support a acting directly in the brain. 2) Whether PYY(3–36) improves meal-
role for central NPY2R signaling in the effects of RYGB, it related glycemic control is uncertain. 3) PYY(3–36) appears to slow
gastric emptying via a direct endocrine effect on the stomach; whether
should be noted that the test was done 5 mo after surgery, vagal-vagal reflexes contribute is unknown. Solid lines indicate well es-
when RYGB and sham-operated animals were eating simi- tablished effects, and dashed lines indicate less well established
lar amounts. It is possible that the outcome may have been effects.

STEINERT ET AL.
gastric emptying via the ileal brake mechanism, to the inhi- won is not a criticism of the strategy. Rather, criteria for
bition of eating, and to the control of meal-related glycemia, physiological function should continue to guide GI hor-
but the evidence that these are physiological actions re- mone research. Identifying truly physiological endocrine
mains thin. Similarly, PYY(3–36)’s role in RYGB remains functions of GI hormones can only facilitate understanding
unclear. This modest progress may be due in part to the of eating, GI motor function, and meal-related glycemic
difficulties of PYY(3–36) research, including the low control and development of therapies for their disorders.
threshold for eliciting illness with PYY(3–36) infusions, the
lack of NPY2R antagonists for human use, and the possi- Perhaps the most pressing issue facing ghrelin, CCK,
bility of neuropod PYY signaling. GLP-1, and PYY(3–36) physiology is the need to determine
the roles of non-endocrine, i.e., local, signaling, which has
been implicated in several of the effects reviewed. The need
VII. DISCUSSION to develop methods enabling tests of local-signaling hy-
potheses against the criteria of TABLE 2 is especially urgent.
The act of eating sets in motion an intricately coordinated As mentioned in section IVD, intraintestinal hormone infu-
series of GI responses that, via central and peripheral influ- sions might selectively target the lamina propria (147), and
ences, contribute importantly to the control of eating and hormone concentrations in the lamina propria can be esti-
meal-related glycemia. The control of secretion of GI hor- mated from assays of lymph. The temporal resolution of
mones by small-intestinal nutrient sensing is a cornerstone lymph assays, however, is poor due to its slow flow. Nor
of these functions. The hormones control exposure of the have the results of tests of meal-related hormone changes in
small intestine to nutrients via their effects on GI motility, the lymph been straightforward. For example, post-meal
especially gastric emptying, and thereby modulate their concentrations of GLP-1 were reported to be ⬃6-fold
own secretion. Here we reviewed the nutrient-secretory higher in lymph than in hepatic portal-vein plasma in rats
controls and contributions to eating, meal-related glycemia, (178) and ⬃8-fold higher in lymph than in orbital-plexus
and GI motility of ghrelin, CCK, GLP-1, and PYY(3–36), in plasma in mice (553), but ⬃10-fold lower in lymph in he-
healthy-weight and obese humans as well as in RYGB pa- patic portal-vein plasma in swine (308).
tients. The primary focus was on normal endogenous or
“physiological” endocrine function in humans because cur- An additional, related challenge for GI-hormonal physiol-
rently available methods make its determination feasible ogy is to encompass the emerging picture of integrated hor-
(TABLE 2). monal and electric signaling in the GI tract. Electrically
excitable GI cells form what Bohórquez and Liddle (91) call
As TABLE 5 indicates, despite considerable research effort, the gut connectome, comprised of enteroendocrine cells,
at present there are many more questions than answers neurons and glia of the enteric nervous system, intrinsic GI
regarding ghrelin, CCK, GLP-1, and PYY(3–36) as physio- neurons, and peripheral ganglia innervating the GI tract.
logical endocrine signals in humans in the functions reviewed. Finally, a third challenge is to better link GI-hormonal phys-
Indeed, only CCK has been fully established as a physiological iology to the study of information processing in the brain,
endocrine control of eating and only GLP-1 as a physiological
endocrine control of meal-related glycemia in healthy-weight
individuals. There is incomplete support for endocrine roles of
CCK in meal-related glycemia and gastric emptying, for Table 5. Physiological status of ghrelin, CCK, GLP-1, and
PYY(3–36) in the endocrine control of eating, GI motility, and
GLP-1 in eating and gastric emptying, and for PYY(3–36) in
meal-related glycemic control in healthy humans
gastric emptying in humans. Moreover, animal research fills
only a few of the gaps indicated in TABLE 5 (an important Meal-Related
exception is that GLP-1R antagonism does increase eating in Eating GI Motility* Glycemic Control
rats under many conditions; see sect. VD). PD/A PD/A PD/A
In view of this decidedly modest estimation of the state of Ghrelin ?/? ?/? ?/?
proof of physiological endocrine function for ghrelin, CCK, CCK YES/YES Yes/Yes† YES/No
GLP-1, and PYY(3–36), one may question whether the cri- GLP-1 YES/No‡ Yes/Yes YES/YES
teria for physiological function (TABLE 2) are overly rigor- PYY(3–36) No/? Yes/? ?/?
ous or whether the criterion-based approach is misguided. Experimental support for the two cardinal criteria of physiological
The answer to each question is no. As reflected in TABLE 1, endocrine function, i.e., the “physiological-dose” criterion (PD) and
criteria for endocrine function have evolved in step with “antagonism” criterion (A), is rated as convincing (YES), partial (Yes),
negative (No), or unknown (?) for each hormone and function. See
advances in understanding and methodology during the text for details and references. *GI motility refers to gastric emptying
century-plus history of endocrinology and have shaped the and small-intestinal motor function. †Cholecystokinin (CCK) antago-
logical and programmatic course of endocrinology and its nism slowed gastric emptying of liquid food, but not solid food. ‡In
two studies (489, 714), premeal administration of the GLP-1 recep-
contributions to medical diagnosis and treatment (59, 292, tor antagonist exendin-9 failed to increase eating, although in one
449, 489, 610, 833). That knowledge at each stage is hard study (714) subjective ratings of appetite increased.

as understood using functional imaging methods in humans Unfamiliar Food Same Food,
and neuropharmacological and molecular-genetic methods Now Familiar
in animals. Present progress in humans is limited largely to -20%
studies of the telencephalic mechanisms of food hedonics, -40%
which have been reviewed elsewhere (references are given in
sect. IA). Advances in the spatial resolution of functional
imaging methods should allow this kind of work to address
the diencephalic and brain-stem mechanisms that are
clearly crucial for the effects of GI hormones on other as-
pects of eating as well as for the control of GI motility and
metabolic function. Increased back-and-forth translation Saline CCK Saline CCK
between human and animal studies should also accelerate FIGURE 12. A thought experiment depicting how learning may
progress in unraveling central mechanisms mediating the influence the control of eating by GI hormones. Left: when an indi-
vidual is served a palatable but unfamiliar food, meal size is deter-
functions of ghrelin, CCK, GLP-1, and PYY(3–36).
mined mainly by unconditioned satiation signals related to gastric
volume, CCK and GLP-1 secretion, etc., as discussed in the review.
Future research should also widen the range of designs used in Under these conditions, CCK infusion during the meal might exert its
GI hormone physiology. Studies of meal size and timing in full unconditioned effect, indicated by the 40% reduction in meal
particular have used remarkably similar experimental ap- size. Right: if the same individual is tested after extensive experience
eating the test food, meal size might be the same as initially, but will
proaches, which may contribute to some of the negative data now be under the control of conditioned responses such as expected
reviewed. As discussed in section IB2, few GI hormone-infu- satiation (111), portion-size estimation (629), etc., that override
sion studies have interrogated parameters other than peak unconditioned signals, and because conditioned eating controls are
plasma levels. Studies of rate ascent of plasma hormone con- resistant to physiological feedback, the same CCK infusion might
centration, the timing of the infusion in relation to the course now reduce meal size less, indicated by the 20% effect.
of the meal or intermeal interval, or other parameters may

unveil physiological effects or explain some apparent para-
influence the GI responses under study, including BMI
doxes, such as why apparently physiological doses of PYY(3–
range, sex, age, race, duration of obesity, age of obesity
36) elicit illness (see sect. VID). Similarly, few studies address
onset, pattern of adipose-tissue distribution (intra-abdomi-
synergistic effects (268). Gastric volume may synergize with
nal, abdominal subcutaneous, gluteo-femoral subcutane-
pharmacological doses of CCK or GLP-1 to elicit satiation (see
ous, etc.), gustatory capacity, dietary habits (large meals,
sect. IID), but whether this reflects a physiological synergy has
snacking, habitual levels of sugar and fat intake, etc.), eat-
not been studied. Synergy analyses may also illuminate some ing traits (dietary restraint, binge-eating propensity, etc.),
failures of antagonist effects. For example, failures of GLP-1R and a host of additional psychological traits (in addition to
antagonism to increase eating in humans may be due to in- the discussion of these in the preceding sections, see Refs.
creases in glucagon or PYY(3–36) rather than the absence of a 32, 38, 40, 60, 498, 522, 706, 729, 817). Although studies
satiating effect of GLP-1 (see sect. VD), and multi-antagonist with sufficient power to resolve the influence of such a far-
approaches may provide useful tests of this hypothesis. Adap- rago of factors are rare, positive results (e.g., Ref. 5) encour-
tation to consumption of particular food types can affect gas- age the view that the issues are tractable. Alternatively, one
tric emptying (see sect. IIA) and, presumably, other GI hor- may isolate and study specific subsets of individuals. One
mone-mediated responses. Finally, experience eating leads to approach to this is exemplified by the study of de Krom et
learning of several types (e.g., Refs. 68, 80, 111, 155, 188, 321, al. (192) of obese individuals who habitually took unusu-
602, 675, 723, 813). Such learning may overshadow uncon- ally large meals or unusually frequent snacks. A number of
ditioned GI-hormonal effects, despite the fact that these were multivariate subgroup-analysis methods also can be used to
probably the basis for the learning in the first place. A hypo- search for reliable variation in the absence of a phenotypic
thetical example is shown in FIGURE 12. In sum, both im- or genetic starting point (384). One may also search directly
proved methods and more varied experimental approaches for consistent individual differences in responses to GI hor-
are likely to enlarge the current restricted view of the contri- mones. This can be done using the repeated-randomization
butions of ghrelin, CCK, GLP-1, and PYY(3–36) to eating and design, in which trials are repeated in the same individuals
meal-related glycemic control. to identify subgroups with consistently larger or smaller
responses (455), which then can be used in mechanistic
We find little evidence that pathophysiology of ghrelin, follow-up studies. Although not a focus here, synergistic
CCK, GLP-1, or PYY(3–36) function contributes to obe- interactions involving GI hormones, such as those among
sity, with the exception of rare individuals bearing genetic CCK, GLP-1, amylin, and leptin (775, 776), are promising
polymorphisms. But the extremely heterogeneous nature of platforms for development of obesity therapies. Similarly,
human obesity should caution against a strong interpreta- the expanding roster of molecular nutrient sensors that con-
tion of these negative data. The participants in obesity stud- trol secretion of multiple GI hormones (TABLE 4) seems to
ies often have wide ranges in several variables that may present especially attractive targets. Finally, as mentioned

STEINERT ET AL.
in several sections, the potential of GI hormones in obesity DISCLOSURES

pharmacotherapy does not depend on whether or not they
contribute to obesity pathophysiology. R. E. Steinert is employed by DSM Nutritional Products.
There is no conflict of interest with regard to the content of
RYGB and related bariatric-surgery procedures substan- the paper.
tially decrease ghrelin secretion and increase CCK, GLP-1,
and PYY(3–36) secretion, especially in the first months after
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Physiol Rev 97: 411– 463, 2017

Published December 21, 2016; doi:10.1152/physrev.00031.2014

GHRELIN, CCK, GLP-1, AND PYY(3–36):

Steinert RE, Feinle-Bisset C, Asarian L, Horowitz M, Beglinger C, Geary N.

I. INTRODUCTION 411 century. These discoveries provided a novel signaling mech-

0031-9333/17 Copyright © 2017 the American Physiological Society 411

412 Physiol Rev • VOL 97 • JANUARY 2017 • www.prv.org

It has long been known that meal-stimulated insulin release

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pre- and postsynaptic proteins, and rabies virus moves ret-

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duce semi-solid chyme. When chyme particles reach a size

Ghrelin ? (⬍0.3)* 441, 759 40 60

416 Physiol Rev • VOL 97 • JANUARY 2017 • www.prv.org

Supraphysiological PYY(3–36) infusions slowed gastric

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physiological-dose criterion (criterion 2, TABLE 2) for hav- A Meal 1 IMI Meal 2

FIGURE 5. Gastric volume, gastric emptying, and ghrelin, CCK,

418 Physiol Rev • VOL 97 • JANUARY 2017 • www.prv.org

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The mechanisms stimulating ghrelin secretion during

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F. RYGB FIGURE 7 summarizes ghrelin physiology around meals.

FIGURE 7. Some features of ghrelin

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300 1500 1500

200 1000 1000

100 500 500

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G. Summary CCK 1 Satiation

CCK is secreted in response to the products of carbohy-

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tively reconstituted in the pancreas displayed normal oral F. RYGB

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PYY is also expressed in the endocrine pancreas, where

PYY(1–36) activates several neuropeptide Y-family recep-

Difficulties in assaying PYY(3–36) complicate studies of its

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C. Eating Only one study of the satiating effect of intrameal PYY(3–

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There are several reports that postprandial plasma PYY

We know of only one test of the eating-inhibitory effect of

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of the meal or intermeal interval, or other parameters may

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