NEUROBIOLOGY

OF APPETITE

Aditya Kumar Sarkar

Post Graduate Trainee
Department of Psychiatry
Medical College, Kolkata
 Satiety signals
Introduction Hunger as Addiction

CONTENTS Hypothalamus Neurocircuitry of

eating disorder
Pathway of
Leptin/Ghrelin
Conclusion
Hedonic System Reference
 INTRODUCTION
Appetite comprises the complexly determined and highly
individuated phenomena of eating and the subjective
phenomena surrounding it.

Appetite: the integrated response to the sight, smell, thought,

or taste of food that initiates or delays eating.

Hunger: the painful sensation caused by a lack of food that

initiates food-seeking behaviour.

Satiation: the feeling of satisfaction; and fullness that occurs

during a meal and stops eating.
 Behavioural Neuroscience of Eating
Three general approaches-
(1) Input approaches- Environmental and experiential contingencies and the exteroceptive
stimuli and interoceptive sensory signals regulate eating behaviour.
Exteroceptive stimuli- Stimuli whose meaning is learned as well as a few innately meaningful
stimuli, the hedonic significance of sweet taste.
Interoceptive stimuli- Circulating levels of hormones and metabolites.

(2) Network approaches-The central neural networks that integrate inputs and produce the
motivational processes that drive eating.

(3) Motor approaches- Neural control of the movements of eating, often called the microstructure
of eating. Food is licked, sucked, bitten, or masticated prior to being moved by lingual and palatal
movements to the oropharynx and swallowed.
 Appetite Is a Network Function
(1) There may be no brain locus where all neural signals controlling appetite converge.
(2) It is unlikely that a neural basis for a unitary motivational process for appetite will
be found. (3) Controls of eating that are elaborated in different parts of the network
may not always operate in a coordinated manner.

The Meal is the appropriate unit of analysis for both functional and
physiological analyses of appetite. The meal is also the biological unit of eating.

The regulation of eating is a complex neurophysiological process influenced by

environmental, genetic, and hormonal factors. Appetite and feeding are controlled by
two interacting systems-
• Homeostatic System- a person gets enough calories to survive.
• Hedonic System- the pleasure and reward aspects of eating.
 Homeostatic
System

Homeostatic System simply is

drive for feeding, need for
calories.
It is important first to understand
the Brain mechanisms that support
the homeostatic drive for feeding.

‘Satiety centre’- The

ventromedial hypothalamic
nucleus (VMN)
‘Hunger centre’-Lateral
hypothalamic area (LHA)
Simple Schematic Diagram of Homeostatic System
BRAIN MECHANISMS
OF APPETITE
Eating is mediated by a complex,
anatomically diffuse neural network
that extends from the caudal brainstem
to the frontal lobes of the cerebral
cortex.

Main Structure- Hypothalamus

Supportive Structure- Brain stem and
Telencephalon.

H, hormones; M, metabolites; SVA, spinal visceral afferents;

CPG, central pattern generator
 Hypothalamus
The hypothalamus, a small area of
the brain located just below the
thalamus, is the regulating center
of appetite and energy
homeostasis.

Hypothalamus Structure Involved in Appetite Regulation

 Continuations…
The ARC is considered to be a hypothalamic area
primarily sensing peripheral metabolic signals.

Anatomical importance of ARC-

 Adjacent to the median eminence, a
circumventricular organ having defective
Blood-brain barriers (BBB). Thus, circulating
hormones and nutrients can access the ARC without
passing the BBB.
The ARC surrounds the Third Cerebroventricle.
Hormones and nutrients in the cerebrospinal fluid
can diffuse into the extracellular fluids of the
ARC.
 Continuations…
In ARC two population of neurons -
One expresses-
α-melanocyte–stimulating hormone (αMSH) as
a neurotransmitter; stimulated by leptin and
inhibited by ghrelin.
The other one expresses
Agouti-related peptide (AgRP), Neuropeptide Y
(NPY), and γ-amino butyric acid (GABA) as
neurotransmitters; inhibited by leptin and
stimulated by ghrelin.
The two populations of ARC neurons have
mutually inhibitory connections.
 Continuations…
The paraventricular nucleus of the hypothalamus
(PVN) that express oxytocin (OT), corticotropin-
releasing factor (CRF) and αMSH as
neurotransmitters.
 In the lateral hypothalamic area (LHA) that express
orexin (OR) and melanin-concentrating hormone
(MCH) as neurotransmitters.

αMSH neurons stimulate PVN neurons, and

AgRP/NPY/GABA neurons inhibit PVN neurons.
αMSH neurons inhibit LHA neurons and
AgRP/NPY/GABA neurons stimulate LHA neurons.

If the net balance of activity in this network is to

stimulate the LHA neurons, eating is stimulated If the
net balance of activity in this network is to stimulate
the PVN neurons, eating is inhibited.
Brainstem
The brainstem is another key brain area involved in regulation.
Satiety signals from the gastrointestinal (GI) tract primarily relay
to the Solitary tract nucleus (NTS) through the sensory vagus
nerve, a major neuronal link between the gut and the brain.

The brainstem also contains the lower motor neurons that

produce eating and swallowing movements.

Telencephalon
Telencephalic contribution to appetite is the
Telencephalic reward network

Subcortical areas (e.g., NAc, Ventral pallidum )

Cortical areas (e.g., Limbic,orbitofrontal, anterior
cingulate, opercular, and insular cortex).
Most of these structures receive dopaminergic,
noradrenergic, and serotonergic inputs.
Adiposity Signals:
Leptin and Insulin
Model showing how a change in
body adiposity is coupled to
compensatory changes of food
intake.

Leptin and insulin are adiposity

signals, secreted in proportion to
body fat content, which act in the
hypothalamus to stimulate
catabolic, while inhibiting anabolic,
effector pathways.
 Mechanism and
Receptor of Insulin
and Leptin

Insulin-receptor substrate (IRS)-1,which is present in

neurons and in peripheral tissues, The neuronal protein
encoded by the Tub gene is also tyrosine-
phosphorylated in response to activation of the insulin
receptor.

Unlike insulin receptors, leptin receptors are members

of the cytokine-receptor superfamily and do not have
intrinsic tyrosine kinase activity. Activated JAK
phosphorylates members of the Signal transduction and
transcription (STAT) family of intracellular proteins
Role of Arcuate nucleus
neurons in Adiposity
signaling

a)Activity of leptin/insulin-sensitive
adiposity signaling pathways in
hypothalamus under conditions of
leptin/insulin deficiency.

b)Increased action of leptin/insulin in

arcuate nucleus inhibits the
NPY/AGRP anabolic pathway and
stimulates the POMC catabolic
pathway, resulting in reduced food
intake and anorexia
 Continuations…

NPY/AGRP(Green) and POMC/CART (Red)neurons in the

arcuate nucleus, adjacent to the third ventricle, are
first-order neurons in the hypothalamic. NPY release in the PVN
and LHA/PFA regions stimulates eating, whereas release of alpha- Orexigenic refers to molecules that
MSH (derived from POMC) in the PVN has an anorexic effect. promote increased energy intake;
CART: Cocaine- and amphetamine-regulated transcript Anorexigenic implies the opposite.
A Central Common Pathway for Driving of Feeding:
Orexin and Melanin Concentrating Hormone

• Orexin – Hypocretin these peptides are produced

by a very small population of cells in the lateral
and posterior hypothalamus.
• MCH neurons are mainly concentrated in
the lateral hypothalamic area.

• MCH and orexin neurons have very similar

diffuse projection patterns to various part of
Diagram showing neuronal axons containing NPY and Brain.
alpha-MSH from the arcuate nucleus (ARC) innervating
the PVN, LHA and PFA (adjacent to the fornix). • Several neuropeptides like CRH, TRH, Oxytocin
Candidate second-order neurons include those that synthesized in PVN neurons reduce food intake.
express TRH, CRH and oxytocin (OXY) in the PVN
(which cause decrease feeding), and neurons
that express orexins and MCH in the PFA and LHA
(which increase feeding).
 Continuations…
Other important function of MCH and Orexin
1)The MCH and Orexin neurons include the
brainstem motor systems that support behaviors
like chewing, licking, and swallowing.

2) Innervate the sympathetic and for a

parasympathetic preganglionic nuclei in the
medulla and the spinal cord- Salivation,
esophageal and gastric motility, gastric acid
secretion, and regulation of the secretion of
pancreatic hormones, including insulin and Simplified scheme of the role of Melanocortins in food intake.
BNST, bed nucleus of the stria terminalis; Acc, accumbens; CeA,
glucagons.
Amygdala; PVN, paraventricular nucleus of the hypothalamus;
LH, lateral hypothalamus; DMH, dorsomedial nucleus of the
hypothalamus;ARC, arcuate nucleus; PB, parabrachial nucleus;
NTS, nucleus of the tractus solitarius; DMV, dorsomotor nucleus
of the vagus.
 Continuations…
3)MCH and Orexin neurons target the
noradrenergic locus coeruleus, the serotoninergic
dorsal and median raphe nuclei, and the
histaminergic tuberomammillary nucleus, which
together constitute an ascending arousal system
directly produce a bout of feeding.

4) MCH enhances the activity in the nucleus

accumbens, in the rewarding aspects of feeding,
play a unique role in enhancing the hedonic value
of food.
 Hedonic System
Though food consumption serves a
homeostatic function, eating can also be an
extraordinarily pleasurable experience. If
feeding were controlled solely by homeostatic
mechanisms, most of us would be at our ideal
body weight, and which constitute pattern
generators for these and people would
consider feeding like breathing or elimination,
a necessary but unexciting part of existence.

The lateral hypothalamus, which coordinates

these motivation signals and links the
homeostatic system with the hedonic system
 Gastrointestinal
Signaling of Satiety
The brain receives a wide variety of signals from the
gastrointestinal tract. Afferent signals carried by the vagus nerve
include indications gastric stretch as well as levels of glucose
and lipids in the liver.
Sensory terminals carrying this information medial and
dorsomedial parts of the nucleus of the solitary tract.

Cholecystokinin
CCK is secreted from I-type enteroendocrine cells in the
duodenum and small intestine to intestinal lamina propria where
it binds to CCK receptors on the vagus nerve terminal,
transferring satiety signals to the hypothalamus via the
brainstem and pontine parabrachial nucleus.

There are two different subtypes of CCK receptors, CCK-A and

CCK-B. CCK-A is primarily expressed in the GI tract, while
CCK-B is predominant in the CNS. Mainly act as anorexigenic
agent.
 Continuations…
Peptide tyrosine-tyrosine (PYY)
PYY is secreted postprandially from the L cells of the ileum, colon, and
rectum mainly after heavy meal as a form of PYY1-36 which is
rapidly metabolized to PYY3-36 by the dipeptidyl peptidase (DPP)-4 in
circulation.
Circulating PYY3-36 binds to the Y2 receptor on presynaptic terminals
of hypothalamic NPY/AGRP neurons, which results in inactivation of
NPY/ AgRP-producing neurons leading to decrease intake of food.

Pancreatic polypeptide (PP)

PP secreted from pancreatic islet PP cells via a vagal-mediated
mechanism after heavy meal. PP has anorexigenic effect via the Y4
receptor in the brainstem and hypothalamus.
 Continuations…
Glucagon-like Peptide-1
Glucagon-like peptide-1 (GLP-1) is produced by
enteroendocrine L-cells, which are found in both
small and large intestine, and by a small population
of neurons in the NTS. Secreted GLP-1 is rapidly
inactivated by dipeptidyl peptidase-IV (DPP-IV), a
proline/alanine specific peptidase found on the
luminal surface of capillary endothelial cells, in the
liver, and in the blood.
GLP-1 secretion and plasma levels are elevated for
hours after GLP-1 may function as a postprandial
satiety via or across-meal satiety signal afferents
abdominal vagus.
 GI endocannabinoids system
The central and peripheral endogenous cannabinoid
Continuations… system appears to play a role in feeding regulation.
Endocannabinoid receptors, CB1 and CB2, are
expressed in the GI tract suggesting that endogenous
endocannabinoids may have an orexigenic effect.

Oxyntomodulin (OXM)
OXM is produced from pre proglucagon along with
GLP-1 in intestinal L cells and has modest
anorexigenic actions
  Ghrelin is a peptide hormone synthesized and
released primarily by enteroendocrine cells in
the stomach and proximal small intestine.

Ghrelin  Plasma levels are high in the morning,

decrease after meals, and increase during
inter meal intervals.
 The site of action for ghrelin on feeding is
thought to be the hypothalamus arcuate
nuclei on Neurons of alpha MSH and AgRP,
NPY. Ghrelin with Leptin has a strong action
both these interconnective sites.
 Satiety signals
control Meal size
Adiposity signals, leptin (secreted by
adipocytes) and insulin (secreted by the
endocrine pancreas in proportion to
adiposity), interact with central autonomic
circuits regulating meal size.

Leptin and insulin are proposed to

stimulate a catabolic pathway
(POMC/CART neurons) and inhibit an
anabolic pathway (NPY/AGRP neurons)
that originates in the arcuate nucleus
(ARC).
 Continuations…
These pathways project to the PVN and
LHA/PFA, where they make connections
with central autonomic pathways that
project to hindbrain autonomic centers
that process satiety signals.
Net neuronal output from the NTS and
other hindbrain regions leads to the
termination of individual meals, and is
potentiated by catabolic projections from
the PVN and inhibited by input from the
LHA/PFA.
Reduced input from adiposity signals,
therefore, increases meal size by reducing
brainstem responses to satiety signals.
A Central Common Pathway for
inhibition of Feeding: The
Melanocortin System

MC4R agonists decreases food intake.

MC receptor antagonist or inverse agonist
AgRP results in increased food intake.
The leptin-responsive POMC/CART neurons
in the arcuate nucleus cause inhibition of
feeding by means of the actions of alpha-MSH
on melano-cortin 3 and 4 receptors (MC3-Rs
MC4-Rs).Because AgRP is an endogenous
antagonist of alpha MSH.
 Gustatory Mechanisms for
Regulating Feeding
• Two Brain stem relay-
First is in the nucleus of The solitary tract and
Second is in The parabrachial nucleus.The parabrachial
nucleus turn projects to a gustatory relay nucleus in the
thalamas as well as to the lateral frontal cerebral cortex, the
central nucleus of the amygdala, and lateral hypothalamic
area.

• The Role of INSULA-

The Insula in multimodal processing of food sensations. The
anterior insula is referred to as gustatory cortex, because it is
the first cortical relay of information from taste receptors in
the oral cavity
 Noradrenaline
Noradrenaline is synthesized in the dorsal vagal
complex and the locus ceruleus. Increased
noradrenaline signaling in the PVN or other
hypothalamic areas may therefore contribute to
increase intake of food induced by leptin deficiency.
Monoamine A hypothesis- Noradrenaline as an anabolic effector in
the CNS control of energy homeostasis.
Neurotransmitters
Serotonin
The serotonin system is comprised of dorsal raphe
nuclei that project widely throughout the brain. 5HT
signaling via the 2C receptor has been implicated in
the eating-inhibitory effects of CCK, GLP-1, leptin.
 Dopamine
Mesolimbic dopamine pathways (comprised of cell bodies in
the substantia nigra and ventral tegmental area that project to
the nucleus accumbens, striatum and cerebral cortex) seem to
contribute to the ‘rewarding’ aspects of consuming palatable
foods. This network is important in hedonic controls of eating.

Continuations… Dopamine has different influences on eating-

In Nucleus Accumbens it stimulates eating.

In The peri fornical hypothalamus it inhibits eating
(a phenomenon potentially explaining the clinical finding that
neuroleptics that antagonize dopamine increase body weight,
apparently by increasing food intake).
Hunger as Addiction
 According to this model four heavily interconnected
structures (shown in gray) the amygdala/hippocampus,
insula, orbitofrontal cortex (OFC), and striatum are the
central elements in the control of appetitive behavior. As
a group these structures are involved in-
(1) learning about (food) rewards;
(2) allocating attention and effort towards (food) rewards;
(3) setting the incentive value of stimuli in the
environment;
(4) integrating homeostatic information about energy
stores and gut contents with information about the outside
world (such as the availability of food). Homeostatic and
gastrointestinal information is conveyed by circulating
hormones and nutrients, acting primarily on the
hypothalamus.
 Neurocircuitry of
Eating Disorder
ANOREXA NERVOSA
(1)Fear of Food -The fear circuitry-the amygdala,
hippocampus, insular cortex, anterior cingulate cortex (ACC),
striatum, and prefrontal cortex,(PFC) regions.
(2)Anxious Temperament
(3)Pathological Fear Learning- Bilateral amygdala, the ACC,
hippocampus, and the insular cortex, inhibitory projections
from the medial PFC/orbitofrontal cortex (OFC) to the
amygdala.

(4)Compulsivity - A decreased activation of fronto-striatal

circuits, including the ventral striatum, ACC, and
supplementary motor area (SMA), underlie this impairment.
 Bulimia Nervosa and Binge Eating Disorder

1. Impulsivity- Impulsivity is characterized by a combination of

heightened sensitivity to reward and impaired inhibitory control.
Continuations… ACC/Ventromedial Prefrontal Cortex, Ventral Striatum and
Thalamus.

2.Food Reward-
• Wanting-VTA to nucleus accumbens (NAc) signaling within
dopaminergic mesolimbic circuits.
• Liking-Sensory information from the gustatory cortex, comprising
the insula/frontal operculum (primary gustatory cortex), the OFC
(secondary gustatory cortex), and the somatosensory cortex.

3. Loss of Inhibitory Control- Right lateral PFC and dorsomedial

frontal cortex (pre-SMA). These two prefrontal regions work
together and send the stop signal to the basal ganglia, which inhibits
the behavioral output of the primary motor cortex.
 There is a continuous interaction between Homeostatic and Hedonic
System of feeding. Physiological modulator ( Exercise, Sex,
Individuality, Flavour hedonics, Innate and Learned hedonics,
Circadian Rhythm) and Psychological factors (Aggression, Stress,
Anxiety, Reward) have their own effect on appetite.

Arcuate Nucleus, Brain Stem and Telencephalon are the main region
in CNS.

CONCLUSION Leptin/Insulin, Ghrelin/Leptin, Orexin/Melanin concentrating Hormone

contribiute main feeding and satiety signaling pathway. Others Homeostatic
and Satiety signals like CKK, PYY, Blood Glucose Level, Ghrelin.

In summary, a clear and comprehensive understanding of feeding-reward

interactions is far from being realized, although many pieces of the overall
puzzle are becoming increasingly well understood.

We need a greater insight into the brain systems underlying normal

everyday emotions and motivations regarding eating behaviour.
 1. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry, 10th
edition.

2. Nature Review Article Central nervous system control of food intake and
body weight- G. J. Morton1, D. E. Cummings, D. G. Baskin G. S. Barsh &
M. W. Schwartz
3. Nature Insight Review Article-Central nervous system control of food
intake-Michael W. Schwartz, Stephen C. Woods, Daniel Porte Jr, Randy J.
REFERENCES Seeley & Denis G. Baskin

4. The Need to Feed: Review Homeostatic and Hedonic Control of

Eating-Clifford B. Saper, Thomas C. Chou and Joel K. Elmquist
5. The neurobiology of appetite: hunger as addiction- A Dagher

6. Various internet sites, Review Articles and Lecture Videos.

THANK YOU!