Review

Overnutrition, ectopic lipid and the metabolic

syndrome
Scott M Grundy

Correspondence to ABSTRACT metabolic processes and predisposes to meta-

Dr Scott M Grundy, Internal The metabolic syndrome is a constellation of bolic risk factors.6 Excess lipid in adipose tissue
Medicine, UT Southwestsern
Medical Center, Dallas, TX
metabolic risk factors including atherogenic is called obesity; in other tissues, it is called
75390-9052, USA; scott. dyslipidemia (elevated serum triglycerides, reduced ectopic lipid. In this document, overnutrition
[email protected] high-density lipoprotein (HDL) cholesterol), elevated will be defined as the any excess of nutrient
blood pressure, dysglycemia (insulin resistance and energy that causes ectopic lipid accumulation
Accepted 29 April 2016
elevated serum glucose), a pro-inflammatory state, outside adipose tissue. The essential pathways
Published Online First
18 May 2016 and a prothrombotic state. Most persons with whereby overnutrition drives development of
metabolic syndrome are obese, and usually have ectopic lipid are shown in figure 1. Excess
Copyright © 2016 American
Federation for Medical abdominal obesity. Generally, obesity is a reflection nutrients come from either dietary triglyceride
Research of overnutrition. A current view is that when adipose or carbohydrate. Dietary triglyceride enters the
tissue fails to store all excess nutrients as circulation with chylomicrons. Triglycerides are
triglyceride, lipid begins to accumulate in various hydrolyzed to fatty acids by lipoprotein lipase
tissues (eg, muscle, liver, pancreas, and heart). (LPL); and most of released fatty acids enter
This accumulation is called ectopic lipid. Various adipose tissue, where they are re-esterified to
mechanisms have been proposed whereby ectopic triglyceride. A portion of fatty acids released by
lipid is detrimental in different tissues; these LPL bypasses adipose tissue and enters a variety
derangements induce metabolic risk factors. The of tissues. Adipose tissue releases non-esterified
foundation of the metabolic syndrome thus appears fatty acids (NEFA), which pass into the circula-
to be overnutrition, that is, more nutrient intake tion and likewise reach many tissues. Glucose
than can be safely disposed by lipid oxidation. derived from dietary carbohydrate goes directly
Excess dietary carbohydrate also induces ectopic into the same tissues. When excess glucose is
lipid. Of interest, less than half of obese individuals consumed, it can be converted to fatty acids
develop metabolic syndrome. Through various through a process known as lipogenesis. All car-
mechanisms they adapt to overnutrition so as to bohydrates and lipids are ultimately disposed
minimize lipid overload in tissues, and consequently, by oxidation. At constant body weight, oxida-
prevent the syndrome. tion rates of triglyceride and carbohydrate
equal their intakes, and lipid content of adipose
tissue remains unchanged. An imbalance
The metabolic syndrome is a constellation of between intake and oxidation occurs only
metabolic risk factors including atherogenic dys- during periods of weight gain or loss. These
lipidemia (elevated serum triglycerides, reduced facts are well known, but often are forgotten
high-density lipoprotein (HDL) cholesterol), when the mechanisms for ectopic lipid and
elevated blood pressure, dysglycemia (insulin metabolic syndrome are discussed.
resistance and elevated serum glucose), a Whereas tissue overload by lipid predisposes
pro-inflammatory state and a prothrombotic to metabolic syndrome, and may be necessary
state.1 2 When present in combination, these for its development, it seemingly is not suffi-
factors essentially double the risk for athero- cient. Other factors, acting in local tissues,
sclerotic cardiovascular disease (ASCVD);3–5 appear necessary for the clinical syndrome to
they also increase risk for type 2 diabetes about present. The following briefly discusses the
fivefold.2 Most persons with metabolic syn- origins of ectopic lipid, and considers add-
drome are obese. This implies that overnutrition itional factors that bring out the syndrome.
contributes to the syndrome.6 Still, less than half
of obese individuals manifest multiple metabolic ADIPOSE TISSUE
risk factors.7 Many persons seemingly are able One emerging view holds that adipose tissue
to adapt to overnutrition so as to prevent the protects against accumulation of ectopic lipid
syndrome. The following discussion examines and hence prevents metabolic syndrome
potential mechanisms underlying the metabolic through fat storage.8–11 If excess dietary nutri-
syndrome and considers how the body defends ents could be stored fully in adipose tissue,
against overload of nutrient energy. ectopic lipid should not occur. Thus the meta-
The most plausible, unifying hypothesis for bolic syndrome may reflect insufficient adipose
To cite: Grundy SM. J the pathogenesis of metabolic syndrome is that tissue to store the load of fat imposed upon it
Investig Med overnutrition drives accumulation of excess by a high-calorie diet. The best example of this
2016;64:1082–1086. lipid in organs or tissues; this in turn deranges mechanism is the rare condition called
1082 Grundy SM. J Investig Med 2016;64:1082–1086. doi:10.1136/jim-2016-000155
 Review

adipose-tissue compartment can be discussed briefly relative

to metabolic syndrome. Figure 2 shows apparent magni-
tudes of flow of fatty acids through these compartments.
Truncal adipose tissue correlates better with metabolic
syndrome than does lower body adipose tissue.18–20
UBSQ-AT is the largest component of truncal adipose
tissue.21–23 It predominates in release of NEFA into the sys-
temic and splanchnic circulations;21–23 thus UBSQ-AT
could be a major source of ectopic lipid. Compared to
LBSQ-AT, UBSQ-AT appears to be more insulin resist-
ant;24–26 this means that UBSQ-AT more readily releases its
fatty acids into the circulation, that is, it has higher turn-
over rates of fatty acids.27 Although UBSQ obesity is often
implicated in causation of ectopic lipid, more likely, it just
Figure 1 Major pathways for triglyceride (TG) and carbohydrate acts as a conduit for transfer of excess nutrient fatty acids
(CHO), in the form of glucose, derived from the diet. These
to the circulation, as suggested in figure 1.
pathways are described in detail in the text. NEFA, non-esterified
fatty acids. A high VAT likewise has been strongly associated with
metabolic syndrome.28–34 It is particularly correlated with
hepatic ectopic lipid.35 Fatty acids entering the splanchnic
lipodystrophy.12 13 This is a condition of severe deficiency circulation are destined for the liver. These can come from
in adipose tissue; hence, consumed lipids cannot be UBSQ-AT or directly from splanchnic lipolysis of TGRLP.36
adequately stored in adipose tissue and other tissues Presumably, visceral obesity is a response to a greater flux
become overloaded. This precipitates the metabolic syn- of NEFA through the splanchnic bed.
drome. Theoretically, even in the absence of lipodystrophy, Compared to upper body compartments, LBSQ-AT
the syndrome could occur if adipose tissue storage capacity seems to possess a lower rate of turnover of fatty acids.
is exceeded, even in the presence of clinical obesity. Individuals with predominant lower body obesity have rela-
Adipose tissue is the major site of uptake for lipid tively normal plasma levels and turnover rates for NEFA.27
released during lipolysis of triglyceride-rich lipoproteins Lower body obesity has been postulated to be protective
(TGRLP). These lipoproteins consist of chylomicrons, against the metabolic syndrome.37 More likely, it is rela-
derived from dietary fat, and of very low-density lipopro- tively neutral, rather than being protective, because of its
teins (VLDL), produced by the liver. Fatty acids freed relatively low turnover rate for fatty acids.27
during lipolysis of TGRLP are taken up by adipose tissue When obesity is present, adipose tissue becomes
and are re-esterified as triglycerides. In turn, adipose-tissue inflamed. This inflammation results from invasion by
triglyceride undergoes lipolysis and releases NEFA into the macrophages secondary to adipose-tissue dysfunction.38
circulation. During weight gain, fat storage is positive; at Consequently, the adipose-tissue bed releases inflammatory
constant weight, no net storage of triglyceride occurs. cytokines and prothrombotic factors into the systemic cir-
NEFA release occurs mainly, but not exclusively, in the culation. Release of excess cytokines may induce a general-
fasting state. Its release is regulated mainly by insulin. ized proinflammatory state, which could contribute to both
During fasting, when insulin levels are low, NEFA release is ASCVD39 and diabetes.40 Release of prothrombotic factors
high; conversely, in the postprandial state, when insulin may likewise predispose to acute ASCVD events. A host of
levels are high, NEFA release is suppressed. Thus, when other ‘adipokines’ has been identified.41 Whether these
excess calories are consumed, increased quantities of fatty
acids cycle through adipose tissue.
Increased release of NEFA from adipose tissue in obese
persons is commonly believed to be a cause of metabolic
syndrome. Of course, high NEFA levels are the result of
increased uptake of fatty acids by adipose tissue in response
to overnutrition; elevated plasma NEFA therefore cannot
be blamed on abnormalities in adipose tissue. For example,
with caloric restriction, plasma NEFA levels rapidly decline
despite persistent obesity.14 Indeed, fasting NEFA concen-
trations correlate relatively poorly with body-fat content.15
This finding likely reflects variability in caloric intake
among individuals.
There are three adipose-tissue compartments that have
been linked in various ways to metabolic syndrome. These
are upper-body subcutaneous adipose tissue (UBSQ-AT),
Figure 2 Pathways for fatty acids released by hydrolysis of
lower-body subcutaneous adipose tissue (LBSQ-AT) (glu- triglyceride in triglyceride-rich lipoproteins (TGRLP). See text for
teofemoral fat), and visceral adipose tissue (VAT).16 17 details. Three major adipose tissue compartments are shown:
Upper-body fat, sometimes referred to as abdominal upper body subcutaneous (UBSQ), lower body subcutaneous
fat, actually includes all truncal fat, and represents the com- (LBSQ), and visceral (VAT). The size of the arrows reflects the
bination of UBSQ-AT and VAT compartments. Each magnitude of the flux through each pathway.
Grundy SM. J Investig Med 2016;64:1082–1086. doi:10.1136/jim-2016-000155 1083
 Review

participate in the relationship between obesity and meta- PANCREAS

bolic syndrome remains to be determined. Fatty acids as well as glucose stimulates insulin secretion.53–56
With overnutrition, excess fatty acids entering pancreatic
MUSCLE β-cells likely are one cause of increased insulin secretion and
Overnutrition increases lean body mass as well as adipose- hyperinsulinemia found in obese individuals. In accord,
tissue triglyceride.42 A greater lean body mass occurs in ectopic lipid has been observed in β-cells of obese, prediabetic
many tissues, but especially muscle. This results in greater animal models.57 Over time, ectopic lipid may destroy β-cells
energy expenditure, which should buffer against through overstimulation of insulin secretion and lipotoxiciy.58
ectopic-lipid accumulation. When overnutrition induces The latter effect could account for the apparent ‘insulin
high NEFA levels, muscle uptake of NEFA is enhanced. A exhaustion’ commonly observed in patients with type 2 dia-
greater muscle mass (and mitochondrial number), second- betes. Of interest, MR spectroscopy shows that the pancreas
ary to greater energy intake, defends against ectopic lipid. contains ectopic lipid when diabetes is present, whereas it
But imbalance between NEFA uptake and oxidation by generally is absent when diabetes is not present.59
muscle results in ectopic lipid and contributes to insulin
resistance.43 The latter, of course, predisposes to hypergly- HEART
cemia, an important metabolic risk factor. In many obese persons, ectopic lipid accumulation is found
to occur in and around the heart.60 Several investigations
LIVER suggest that lipid accumulation is detrimental to cardiac
A high caloric intake increases the nutrient load on the function (for a detailed review see reference).61
liver. Like in muscle, high levels of fasting NEFA derived
from adipose tissue raise hepatic uptake of fatty acids. As
CARBOHYDRATE OVERNUTRITION
well, the liver has other sources of fatty acids. Among these
Most evidence supports the concept that fatty acids repre-
are fatty acids released by lipolysis of TGRLP in the
sent the final common pathway to tissue nutrient overload.
splanchnic circulation44 and hepatic uptake of chylomicron
Less attention has been given to the possible untoward
remnants. Further, when muscle is insulin resistant, more
effects of excessive intake of carbohydrate. For example,
glucose is routed to the liver, which stimulates de novo syn-
high-carbohydrate intakes enhance postprandial glycemia,
thesis of fatty acids.45 Thus, hepatic ectopic lipid in one
which itself may be detrimental over the long run.
way or another represents a product of overnutrition.
Postprandial hyperglycemia may cause oxidative stress or
Ectopic lipid in the liver is synonymous with non-
otherwise be glucotoxic in a variety of tissues.62 63 Chronic
alcoholic fatty liver (NAFL). The latter in turn predisposes
overstimulation of insulin secretion induced by dietary
to non-alcoholic steatohepatitis, which can sometimes
carbohydrate could have at least two untoward effects.
produce cirrhosis or liver cancer. NAFL occurs almost
First, β-cell function may be impaired by chronic glucotoxi-
exclusively in obese persons;46 hence overnutrition is an
city;63–65 and second, carbohydrate-induced hyperinsuline-
underlying cause. But many obese individuals are able to
mia may suppress muscle insulin sensitivity.66–68
avoid NAFL,46 presumably by incorporating excess lipid
Hyperinsulinemia associated with excess dietary carbohy-
into VLDL or by enhancing fatty acid oxidation.
drate may be secondary to fatty acids produced by lipogen-
Conversely, in some individuals, these two pathways are
esis in β-cells. Moreover, high-carbohydrate intakes can
sluggish and trap fat in the liver.47
induce lipogenesis in the liver;69 70 fatty acids produced in
An increased load of fatty acids on the liver typically
this way can feed into the final common pathway of
causes overproduction of VLDL particles.48
ectopic lipid accumulation (figure 1). Thus the role of
Overproduction raises plasma triglycerides, provided they
carbohydrate overnutrition in the development of meta-
are not rapidly removed by enhanced lipolysis.48 An eleva-
bolic syndrome should not be overlooked. It is worthy of
tion in VLDL triglyceride is one important metabolic risk
more investigation.
factor. Increased production of VLDL particles can further
raise the plasma apolipoprotein B—another lipoprotein
risk factor. Finally, hepatic lipid overload stimulates the OVERFEEDING STUDIES
synthesis of hepatic lipase,49 an enzyme that degrades HDL One approach to understanding the effects of overnutrition
particles and lowers HDL-cholesterol concentrations. Thus, on the metabolic profile is through overfeeding studies.
an increased lipid load in the liver, which results from over- Many such studies have been carried out.71–76 They indi-
nutrition, is the underlying cause of atherogenic cate that overnutrition produces a deterioration of meta-
dyslipidemia. bolic status, although there is considerable individual
variability in response. Such investigations are potentially
KIDNEY useful for identifying those who are particularly susceptible
Elevated blood pressure commonly occurs with the meta- the development of metabolic risk factors.
bolic syndrome. Hyperinsulinemia is one factor implicated
in causation of hypertension.50 Another contributor may GENETIC FACTORS
be accumulation of ectopic lipid in the renal sinus and peri- The host of genetic factors likely act at tissue levels to influ-
nephric region.51 Renal sinus fat may compress venules and ence the response to nutrient excess. Several genome-wide
lymphatics in the kidney and thus impair blood pressure association studies have been carried out to search for
regulation. Moreover, excess lipid in the perinephric region genes contributing to the metabolic syndrome.77–80 These
may compress the kidneys, induce ischemia and cause studies suggest that multiple different genes act simultan-
hypertension.52 eously to modify metabolic risk factors. But occasionally,
1084 Grundy SM. J Investig Med 2016;64:1082–1086. doi:10.1136/jim-2016-000155
 Review

monogenic or oligogenic factors can predominate. In some Provenance and peer review Commissioned; externally peer reviewed.
cases, genetic abnormalities appear to predispose to ectopic
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