Hypothalamic Regulation of Appetite

Katherine A. Simpson; Niamh M. Martin; Steve R. Bloom

Authors and Disclosures
Posted: 10/08/2008; Expert Rev Endocrinol Metab. 2008;3(5):577-592. 2008
Future Drugs Ltd.

Abstract and Introduction

Abstract
The prevalence of obesity is steadily rising and has huge health and financial implications
for society. Weight gain is due to an imbalance between dietary intake and energy
expenditure and research has focused on trying to understand the complex pathways
involved in controlling these aspects. This review highlights the key areas of research in
the hypothalamic control of appetite. The hypothalamus consists of several nuclei that
integrate peripheral signals, such as adiposity and caloric intake, to regulate important
pathways within the CNS controlling food intake. The best characterized pathways are the
orexigenic neuropeptide Y/Agouti-related protein and the anorexigenic proopiomelanocortin/cocaine- and amphetamine-related transcript neurons in the arcuate
nucleus of the hypothalamus. These project from the arcuate nucleus to other key
hypothalamic nuclei, such as the paraventricular, dorsomedial, ventromedial and lateral
hypothalamic nuclei. There are also projections to and from the brainstem, cortical areas
and reward pathways, all of which influence food intake. The challenge at present is to
understand the complexity of these pathways and try to find ways of modulating them in
order to find potential therapeutic targets.

Introduction
Epidemiology. Globally, the WHO estimates that over 1 billion people are currently
overweight and that over 300 million people are obese.[1] In the UK, the prevalence of
obesity has more than tripled in the past 25 years, and obesity among children has tripled
in a decade.[222] A weight gain of just 1kg has been shown to increase cardiovascular risk
by 3.1% and diabetes risk by 4.5-9%.[2] As expected, obesity-related disorders have also
increased, with 80% of obese adults having at least one or more comorbidities, including
diabetes mellitus, hyperlipidemia, hypertension, cardiovascular disease and certain forms
of cancer.[3,4] Deaths related directly to obesity have been estimated at 320,000 per year in
Europe and 300,000 in the USA.[222]Governments in developed countries now recognize
the potential social and financial burden that obesity will pose in the future. As a
consequence, various reports and strategies have been suggested, particularly in children,
in an attempt to tackle the problem.
Thrifty phenotype hypothesis. The increasing prevalence of obesity is partly attributable
to a lack of exercise and the availability of high-calorie palatable food.[5] Some have also

postulated that sleep deprivation and its effects on gut hormone secretion has a role in the
development of obesity.[6] The concept of the 'thrifty phenotype' hypothesis was first coined
almost 50years ago with the observation that, during the hunter-gatherer days of man,
possession of genes that allowed one to survive despite famine, confered an evolutionary
advantage.[7] Carriers of such genes would be able to store energy more efficiently during
periods of abundant food supply to increase their odds of survival during famine. However,
this 'thrifty genotype' becomes a disadvantage at times of abundant energy supply, such
as that seen in our current Western civilization, resulting in obesity. Family, twin and
adoption studies indicate that obesity is highly heritable, with the estimated genetic
contribution ranging from 60 to 84%.[8] A series of complex systems regulate energy
homeostasis so that sufficient energy is available and bodyweight remains stable.[9] Central
circuits in the brain rely on peripheral signals indicating satiety levels and energy stores, as
well as higher cortical factors, such as emotional and reward pathways. The hypothalamus
is critical in the regulation of food intake and acts as a 'key controller' within neural circuitry
to maintain energy homeostasis. As illustrated in Figure 1, the hypothalamus is an integral
part of the processing of afferent signals, such as those from the gut and brainstem, as
well as the processing of efferent signals that modulate food intake and energy
expenditure. The hypothalamus is subdivided into interconnecting nuclei, including the
arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial nucleus (VMN),
dorsomedial nucleus (DMN) and lateral hypothalamic area (LHA). Early lesioning studies
proposed a 'dual center' hypothesis, whereby the ventromedial hypothalamus acted as a
satiety center and the lateral hypothalamus was a 'feeding center'.[10,11]The dual center
hypothesis has now been replaced by the concept of discrete neuronal pathways, which
are integrated into a complex neural network in which specific orexigenic and anorexigenic
neurotransmitters are released from specific neurons to influence food intake and energy
expenditure. The purpose of this review is to highlight the key players in the hypothalamic
control of appetite, the brain circuitry involved and potential therapeutic targets for obesity.
[ CLOSE WINDOW ]

Figure 1.
Relationship between the brainstem, hypothalamus, cortical areas and reward circuitry
known to modulate appetite control. Gut hormones acting via vagal afferents act on the
NTS in the brainstem, which in turn signals to the hypothalamus. Some gut hormones may
also act directly on hypothalamic nuclei via the circulation and across an incomplete bloodbrain barrier. There are projections from hypothalamic nuclei to the prefrontal cortex,
involved in conditioned taste aversion, as well as reward centers, such as the amygdala
and nucleus accumbens. Leptin is also thought to act directly on the NTS as well as
hypothalamic nuclei, suggesting that it can modulate appetite through different pathways.
ARC: Arcuate nucleus; CCK = Cholecystokinin; GLP = Glucagon-like peptide; LHA =
Lateral hypothalamic area; NTS = Nucleus tractus solitarius; OXM = Oxyntomodulin; PYY
= Peptide YY; PVN = Paraventricular nucleus; VMN = Ventromedial nucleus.

Hypothalamic Regions Important in Appetite Regulation

Arcuate Nucleus
The ARC is a key hypothalamic nucleus in the regulation of appetite. In mice, lesions of
the ARC using monosodium glutamate produce obesity and hyperphagia.[12] Anatomically
related to the median eminence, the ARC is not fully insulated from the circulation by the
blood-brain barrier and, hence, is strategically positioned to integrate a number of
peripheral signals controlling food intake (Figure 2).[13,14] Two major neuronal populations in
the ARC are prominently implicated in the regulation of feeding. One population, localized
more medially in the ARC,[15] increases food intake and coexpresses neuropeptide Y (NPY)
and Agouti-related protein (AgRP). The second population of neurons, coexpressing
cocaine- and amphetamine-related transcript (CART) and pro-opiomelanocortin (POMC),
inhibits food intake and tends to cluster more laterally in the ARC.[16] Neuronal projections
from these two populations then communicate with other hypothalamic areas involved in
appetite regulation, such as the PVN, DMN and LHA.[17-20] This network of neuronal circuitry
can be modulated by peripheral signals, such as leptin and insulin.
[ CLOSE WINDOW ]

Figure 2.
The main hypothalamic nuclei, neuropeptides and pathways involved in the regulation of
appetite. Circulating hormones act on the ARC, which has an incomplete blood-brain
barrier and, hence, can affect downstream pathways, which modulate appetite control. In
the ARC, orexigenic neurons coexpress NPY and AgRP, whereas neurons coexpressing
POMC and CART are anorexigenic. In the ARC, activation of AMPK leads to increased
food intake, an effect that is inhibited by insulin and leptin. AgRP = Agouti-related protein;
AMPK = Adenosine monophosphate protein kinase; ARC = Arcuate nucleus; CART =
Cocaine- and amphetamine-related transcript; CB1 = Endocannabinoid receptor 1; CCK =
Cholecystokinin; DMN = Dorsomedial nucleus; GLP = Glucagon-like peptide; LHA =
Lateral hypothalamic area; MCH = Melanin-concentrating hormone; NPY = Neuropeptide
Y; OXM = Oxyntomodulin; POMC = Pro-opiomelanocortin; PYY = Peptide YY; PVN =
Paraventricular nucleus; VMN = Ventromedial nucleus.

Reward Mechanisms & Hypothalamic Appetite Regulation

Reward mechanisms play a large role in appetite regulation and are thought to
predominantly involve the mesolimbic system in the brain. Conditioned taste aversion
(CTA) and lesioning experiments suggest the orbitofrontal cortex and amygdala are
important in learning and experiencing food and its subsequent effect on food intake.
Neuroimaging studies in humans have shown that pleasant and unpleasant odors activate
different regions of the orbitofrontal cortex and cingulate gyrus, areas that have direct
projections to the hypothalamus (Figure 1). MCH and orexin fibers in the LHA transmit and
receive information from the cerebral cortex.[122] In addition, the LHA receives an inhibitory
input from the shell of the nucleus accumbens, which in turn receives inputs from the
prefrontal cortex.[123-125] Interestingly, there is high expression of CB1 receptors in the
nucleus accumbens and other reward circuitry, such as the hippocampus and medial
forebrain bundle. Furthermore, endocannabinoids have been found to inhibit excitatory
inputs to neurons in the shell of the nucleus accumbens.[126]

Endocannabinoids
Evidence to date suggests that endocannabinoids act as orexigenic signals via
cannabinoid CB1 receptors in the CNS.[127] Blocking CB1 receptors inhibits food intake and
causes weight loss in rodents.[128] The weight-reducing effect of CB1 antagonists (e.g.,
rimonabant) is accentuated in obese animals[129] and has been used in the treatment of
human obesity. CB1 receptors are the most abundant G-protein-coupled receptors in the
mammalian brain and are expressed in key hypothalamic areas regulating appetite, such
as the PVN.[130] CB1 receptors are mainly localized to presynaptic axon terminals and
activated by retrograde signaling of endocannabinoids synthesized and released by the
postsynaptic neurons.

During fasting, hypothalamic endocannabinoid levels increase and subsequently decrease

following refeeding.[131]Cannabinoids administered directly into the VMN increase food
intake[132] and this effect is inhibited by a prior injection of a CB1 receptor antagonist via the
same route. Hypothalamic endocannabinoids are purported to stimulate appetite via CB1
receptors by regulating the expression and release of anorexigenic and orexigenic
neuropeptides. The mechanisms of cannabinoid-induced hyperphagia remain to be
elucidated. However, evidence suggests involvement of both reward processes and
established appetite modulators, such as leptin,[133]glucocorticoids[134] and melanocortins,
[135]
within the hypothalamus.
Recent studies support an interesting relationship between the endocannabinoid system
and CART. Administration of the cannabinoid agonist HU-210 to mice results in elevated
CART immunoreactivity in the ARC, DMN and the shell portion of the nucleus accumbens.
[128]
Interestingly, the CB1 receptor antagonist rimonabant is unable to inhibit food intake in
CART-deficient mice.[128] Furthermore, mice deficient in fatty acid amide hydrolase (FAAH),
the enzyme responsible for the invivo metabolism of the endocannabinoid anandamide,
have reduced levels of CART immunoreactivity in several brain regions implicated in
appetite control, including the ARC and DMN. When FAAH-deficient mice are treated with
rimonabant, CART levels increase toward those seen in wild-type controls.[128]
There also appears to be close interaction between endocannabinoids and opioids with
the finding that the orexigenic effects of an endocannabinoid were attenuated by naloxone,
an opioid antagonist.[136] Interestingly, this interaction between opioids and
endocannabinoids involved in feeding behavior appeared to be localized not at the
mesolimbic system level but, preferentially, at the level of the PVN of the hypothalamus.
This was supported by the finding that rimonabant is able to reduce morphine-induced
feeding only when the opioid is directly injected into the PVN but not into the nucleus
accumbens.[137]
Reward pathways utilize dopamine, opioids, serotonin and noradrenaline neuronal fibers,
which connect the hindbrain and midbrain to the hypothalamus and all are known to affect
appetite when injected into hypothalamic nuclei.[138-141] In addition, orexigenic NPY and
anorexigenic POMC neurons in the ARC have projections throughout the brain, including
the serotonergic system in the raphe nuclei and areas involved in reward, such as the
amygdala.
Nicotine has also been found to affect hypothalamic neurotransmitters involved in appetite
regulation. When nicotine is given to neonatal rats, it causes an increase in nicotine
acetylcholine receptors in the VMN and ARC. In addition to inhibiting weight gain, nicotine
administration also increases ARC NPY, AgRP and POMC mRNA expression[142] and CART
gene transcript levels.[143] These effects are suppressed by the addition of a nicotinic
acetylcholine receptor antagonist.[142]

Adiposity Signals Affecting Hypothalamic Control of Appetite

Adipokines are secreted by adipose tissue and include leptin, adiponectin and resistin.
They are able to mediate their effects centrally via the hypothalamus to affect food intake
as well as energy expenditure.[144-146] Insulin and leptin levels are also proportional to fat
mass and have profound effects on appetite.

Leptin
Leptin is secreted by adipocytes and circulates at concentrations proportional to fat mass.
Rodents and humans lacking leptin (ob/obmice)[147] or the leptin receptor (db/db mice and
Zucker fa/fa rats) are obese and hyperphagic. In humans, the rare condition of leptin
deficiency causes severe obesity,[148] which can be ameliorated by peripheral leptin
administration.[149] However, in nonleptin-deficient obese individuals, chronically elevated
levels of leptin are associated with a leptin-resistant state whereby central circuits in the
hypothalamus are less sensitive to its anorexigenic effects.[150]Whether leptin resistance is
a secondary effect of high circulating leptin levels or actually the primary defect in leptin
signaling remains to be elucidated.
Circulating leptin crosses the blood-brain barrier via a saturable process[151] and binds to
leptin receptors in the hypothalamus.[152]Leptin receptors belong to the class I cytokine
receptor family. These are known to act through Janus kinases (JAKs) and signal
transducers and activators of transcription (STATs). Suppressor of cytokine signaling
(SOCS)3 expression induced by leptin binding to its receptor acts as a negative feedback
mechanism for leptin receptor signaling, and changes in SOCS3 expression are thought to
underlie the phenomenon of leptin resistance. Leptin also activates the insulin receptor
phosphatidylinositol-3-OH kinase (PI3K) pathway suggesting a common pathway.
Downstream signaling of the PI3K pathway involves the adenosine monophosphateactivated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway
and it is proposed that both are important in mediating the effects of leptin in the
hypothalamus. For example, leptin action is inhibited if hypothalamic AMPK is prevented
from falling[153] and mTOR is prevented from rising.[154]
The long form of the leptin receptor, Ob-Rb, is expressed widely within the hypothalamus
but particularly in the ARC, VMN, DMN and LHA. Using viral-mediated gene expression,
chronic leptin overexpression in the ARC, PVN and VMN results in reduced food intake.
[155]
In the ARC, Ob-Rb mRNA is expressed by NPY/AgRP and CART/POMC neurons.
Leptin directly activates anorexigenic POMC neurons and inhibits orexigenic AgRP/NPY
neurons, resulting in an overall reduction in food intake.[70,156] In addition, animals with
raised plasma leptin levels one week after presentation of palatable food showed
significantly greater downregulation of MC4-R expression in the ARC, DMN and VMN.[157]

Insulin
Circulating insulin rises in response to a glucose load and, as with leptin, circulating levels
reflect fat mass. Insulin reaches the CNS via receptor-mediated transport across the
blood-brain barrier. Insulin receptors are widely distributed in the brain, particularly in
hypothalamic nuclei involved in the regulation of food intake. Neuron-specific insulin
receptor-knockout (NIRKO) mice are obese and have increased food intake as well as
elevated plasma leptin and insulin levels.[158] Insulin has an anorectic effect when
administered ICV or directly into the VMN. Consistent with this, insulin antibodies increase
food intake and bodyweight when administered directly into the VMN.[159] ICV-administered
insulin acts via insulin receptors in the ARC[160] and activates insulin receptor substrate
(IRS) proteins and the PI3K pathway. The anorectic effect of insulin may be mediated
through IRS-2, since IRS-2-null mice display increased food intake[161] and IRS-2 mRNA is
highly expressed in the ARC. The precise mechanism by which insulin inhibits food intake
is still unknown. Insulin has been shown to inhibit NPY/AgRP neurons in the ARC.
[20]
However, the anorectic effects of insulin may also reflect an interaction with the
melanocortin system, since insulin receptors are also present on ARC POMC neurons and
ICV administration of insulin increases ARC POMC mRNA expression. Furthermore, the
anorectic actions of insulin are blocked by melanocortin antagonists.[20,162]

Interactions Between the Brainstem & Hypothalamus

Although the hypothalamus could be regarded as the 'gate keeper' of appetite signaling, it
is important to remember that, in addition to input from higher brain centers, the
hypothalamus also receives signals from the periphery (Figures 1 & 2). The deficient
blood-brain barrier of the ARC enables circulating factors regulating appetite to
communicate directly with the hypothalamus. The brainstem is another key CNS appetiteregulation center [163] and peripheral satiety signals can also act directly on brainstem
structures such as the area postrema, which also possesses an incomplete blood-brain
barrier. Extensive reciprocal neuronal projections exist between brainstem and
hypothalamic feeding circuits to provide an alternative pathway through which circulating
satiety factors can communicate with the hypothalamus.[164,165] The vagus nerve is the major
neuroanatomical link between the GI tract and the brain. Cell bodies of afferent fibers of
the abdominal vagus nerve are located in the nodose ganglia, which project onto the
brainstem. Here, the dorsal vagal complex (DVC), consisting of the dorsal motor nucleus,
the area postrema and the sensory nucleus of the tractus solitarius (NTS), interfaces with
hypothalamic and higher centers.[163] A population of POMC neurons exist in the NTS and it
has been shown that over 50% demonstrate activation of STAT-3 in response to peripheral
leptin administration.[166] Hence, the vagus nerve provides an additional pathway via which
appetite-regulatory signals from the periphery can communicate with the hypothalamus to
regulate energy homeostasis.

Gut Hormones
The GI tract is the body's largest endocrine organ and releases a plethora of regulatory
peptide hormones that influence a number of physiological processes. The majority of
these hormones are sensitive to gut nutrient content, and short-term feelings of hunger
and satiety are believed to be mediated, in part, by coordinated changes in circulating gut
hormone concentrations.[167]

Cholecystokinin
Cholecystokinin was the first gut hormone demonstrated to have an effect on food intake.
[168]
CCK is released postprandially and, in addition to local effects within the gut, inhibits
food intake in rodents and humans.[169,170] CCK1 receptor-knockout rats and intraperitoneal
delivery of CCK1 antagonists results in obesity, in part due to hyperphagia.
[171,172]
Interestingly, intraperitoneal CCK administration increases c-fos expression in the
DMN and PVN. Direct administration of CCK into the DMN decreases food intake[173] and
downregulates NPY gene expression.[112,171]

Glucagon-like Peptide-1
The pre-proglucagon gene is widely expressed in the enteroendocrine L cells of the
intestine, pancreas and brainstem.[174] It is cleaved by prohormone convertases 1 and 2 to
produce mainly glucagon in the pancreas, and glucagon-like peptide (GLP)-1, GLP-2 and
oxyntomodulin in the CNS and intestine. GLP-1 is released into the circulation following a
meal in proportion to the calories consumed[175] and acts via the vagus nerve to inhibit food
intake.[176] Central administration of GLP-1 to rats inhibits food intake[176] and activates cfos expression in the ARC, amygdala and PVN.[176,177] GLP-1 receptor mRNA is densely
expressed in the ARC and more than 60% appears to be colocalized with POMC neurons.
[178,179]
Administration of GLP-1 in whole-cell patch-clamp recording increases the
spontaneous action potential firing of POMC neurons in the ARC, an effect that is blocked
by the GLP-1 receptor antagonist exendin 9-39.[178] However, the anorectic effects of GLP-1
appear to involve both the hypothalamus and the brainstem-vagus complex. Systemically
injected GLP-1 induces expression of c-fos in the brainstem and the PVN, but not in the
ARC.[180-182] Administration of exendin 9-39 (a GLP-1 antagonist) directly into the ARC does
not diminish the anorectic actions of peripherally administered GLP-1.[182]Interestingly,
recent work supports a role for hypothalamic GLP-1 signaling in the brain-gut GLP-1
pathway.[183]Following activation of enteric glucose sensors, c-fos expression is increased in
the brainstem solitary tract nucleus, but diminished in the ARC, VMN and DMN. However,
these c-fos expression patterns were not observed in GLP-1 receptor-knockout mice.
Overall, the actions of GLP-1 may be centered more in the brainstem than in the ARC,
since vagotomy or ablation of the brainstem-hypothalamus pathways attenuates the
anorectic effect of GLP-1.[180]

Oxyntomodulin
As with GLP-1, oxyntomodulin is secreted from intestinal L cells postprandially and
reduces food intake when administered peripherally or ICV to rodents.[182] Peripheral
administration of oxyntomodulin activates c-fosexpression in the ARC and its anorectic
effects can be blocked through the use of a GLP-1 antagonist.[182] In mice, manganeseenhanced MRI[184] demonstrates that intraperitoneal injection of oxyntomodulin results in
reduced rate of signal enhancement in the ARC, PVN and supraoptic nucleus, whereas
GLP-1 causes a reduction only in the PVN, yet an increase in the VMN. This suggests that
GLP-1 and oxyntomodulin act via different hypothalamic pathways.

Ghrelin
Ghrelin is produced by the stomach and acts as an endogenous ligand on the growth
hormone secretagogue (GHS) receptor.[185] Although the majority of ghrelin is produced
peripherally, there are ghrelin-immunoreactive neurons adjacent to the third ventricle and
between the DMN, VMN, PVN and ARC. These ghrelin neurons have terminals on
hypothalamic NPY/AgRP, POMC and CRH neurons,[186] as well as orexin fibers in the LHA.
[187]

Ghrelin initiates hunger prior to a meal and ghrelin increases food intake when
administered to patients with cancer cachexia[188] and anorexia associated with renal
failure.[189] Peripheral and central administration of ghrelin increases c-fos expression in
ARC NPY/AgRP neurons and increases hypothalamic NPY mRNA expression.
[190]
Furthermore, ICV NPY and AgRP antibodies and antagonists abolish ghrelin-induced
feeding. Intraperitoneal administration of ghrelin also stimulates c-fos expression in the
PVN.[191,192] When ghrelin is injected directly into the PVN, it stimulates food intake, an effect
that is suppressed by intra-PVN preinjection of a melanocortin agonist.[193] Interestingly,
ghrelin induces an increase in hypothalamic endocannabinoid content in mice.[194] However,
this effect is not seen in CB-1-knockout mice or in normal mice when pretreated with
rimonabant.
Although ghrelin has potent actions on appetite, ghrelin-null mice and ghrelin receptorknockout mice have normal appetite and bodyweight when fed a standard diet[195] but,
importantly, do resist diet-induced obesity.[196,197]This may be due to upregulation of other
systems controlling appetite or could imply that ghrelin only has short-term effects on food
intake, playing a smaller role in the overall regulation of appetite.

Peptide YY
Peptide YY (PYY) is a member of the pancreatic polypeptide (PP)-fold family of peptides
released by L cells in the gut into the circulation following a meal. The PP-fold family
comprises NPY, PYY and PP, which all share a common tertiary structure known as the PP

fold. PYY is cleaved at the N-terminus by dipeptidyl peptidase IV (DPP-IV) to create the
truncated form PYY3-36. Whereas full-length PYY binds to Y1, Y2 and Y5 receptors, PYY336 is relatively selective for the Y2 receptor. Peripheral administration of PYY 3-36 reduces
food intake in rodents and humans and PYY-knockout mice develop obesity.[198,199] In
contrast to peripheral administration, ICV injection of PYY3-36 stimulates food intake,
possibly through Y1 and Y5 receptors in the PVN.
The exact mechanisms underlying the anorectic effects of PYY3-36 are unclear. Several
lines of investigation suggest a direct anorectic action of circulating PYY3-36 on the ARC.
Peripheral administration of PYY3-36 inducesc-fos expression in the ARC and direct
injection of PYY3-36 into the ARC inhibits feeding.[198] It has been proposed that PYY336 exerts its anorectic effect via the Y2 receptor since this is abolished in Y2 receptorknockout mice.[198] The Y2 receptor is highly expressed on ARC NPY neurons and PYY336 may reduce food intake by inhibiting NPY release via autoinhibitory Y2 receptors. PYY336 decreases NPY release and increases -MSH release in vitro from hypothalamic
explants.[198] Electrophysiology studies suggest that PYY3-36 directly inhibits the activity of
ARC NPY neurons, thereby secondarily disinhibiting anorectic POMC neurons.[200]However,
further studies suggest that the anorectic effects of PYY3-36 are more complex than a
simple action on the ARC, since both POMC-null and MC4-R-null mice respond normally
to the anorectic effects of PYY3-36.[201,202] Recent findings support a vagal-brainstem pathway
mediating the effects of PYY3-36 on appetite, since vagotomy or lesioning of the brainstemhypothalamic neuronal pathways abolishes the anorectic effects of peripheral PYY3-36.
[180,203]
This observation, combined with evidence for Y2 receptor expression in the NTS and
nodose ganglion of the vagus nerve,[203,204] has led to the proposal that PYY3-36 may regulate
ARC neuronal activity indirectly via vagal-brainstem pathways.

Pancreatic Polypeptide
The anorectic gut hormone PP is released from the pancreas into the circulation after a
meal and, as with PYY, is released in proportion to calories ingested. Peripheral injection
of PP to rodents and humans reduces food intake.[205-207] Peripheral PP administration
activates neurons in the area postrema of the brainstem, an area with a high density of Y4
receptors, and reduces hypothalamic NPY and orexin mRNA expression.[205,208] By contrast,
when given centrally, PP stimulates appetite and increases hypothalamic NPY expression.
[205]
These contrasting effects of PP on feeding depending on the route of administration
probably reflect differential receptor distribution and activation. The anorectic effect of
peripheral administration of PP is likely to arise from activation of Y4 receptors, whereas
the receptor mediating stimulatory effects on appetite following central injection is unclear.

Nutrient Sensing
There is evidence that the hypothalamus can also sense nutrients and adjust food intake
accordingly.[209] When cellular energy stores are deplete, the enzyme AMPK is activated in

order to increase substrate uptake.[210] In the ARC, activation of AMPK leads to increased
food intake and bodyweight; an effect that is inhibited by both insulin and leptin.
[153]
However, hypothalamic AMPK inhibition is essential for leptin's effect on food intake
and bodyweight.[153]Recent evidence shows that ghrelin activates NPY neurons in the ARC
through an AMPK pathway.[211] AMPK in the VMN also appears to play a key role in the
detection of acute hypoglycemia and initiation of the glucose counter-regulatory response.
[212]
There has also been increasing evidence for a common pathway within the PVN
involving AMPK. Intraperitoneal leptin and lateral ventricle administration of a melanocortin
agonist causes a significant decrease in AMPK activity in the PVN,[153] whereas ICV AgRP
causes an increase.
There are considerable data demonstrating the effects of circulating carbohydrates, lipids
and amino acids in the hypothalamic control of appetite. Hypoglycemia itself stimulates
food intake and the hypothalamus has key glucose-sensing neurons in order to counteract
this.[213] Interestingly, acute hypoglycemia increases hypothalamic NPY and AgRP and
reduces POMC expression.[214]Plasma long-chain fatty acids cross the blood-brain barrier
in a dose-dependent manner and can regulate food intake via the hypothalamus. ICV
administration of the long-chain fatty acid oleic acid inhibits food intake by reduction of
ARC AgRP and NPY expression.[215] Amino acids are also implicated in the hypothalamic
regulation of food intake, and ICV administration of the amino acid leucine reduces food
intake in rats. Leucine is thought to mediate its effect through increased hypothalamic
mTOR activity that reduces ARC NPY expression.[154] Intestinal chemosensors are an
exciting recent area of focus in understanding feed-forward signals to the hypothalamus to
regulate energy intake.[216]

Clinical Therapeutic Applications

In conclusion, the hypothalamic control of appetite is complex and relies not just on
signaling pathways within the brain but also peripheral signals acting via the brainstem and
reward circuitries. As such, there are multiple potential targets for developing anti-obesity
agents.[217] However, due to the complexity of neuronal circuits involved in appetite control,
it is unlikely that targeting one specific pathway will result in prolonged and clinically
relevant weight loss. Understanding and hence modulating several pathways, including
those affecting the brainstem and gut hormone profile, is likely to be a more successful
approach and may provide real hope for effective treatments for obese patients.

Expert Commentary
At present, only two drugs are licensed and endorsed by the National Institute of Clinical
Excellence (NICE) in the UK and the US FDA for long-term therapy against obesity: orlistat
and sibutramine. Final appraisal documentation from NICE has also been published and
recommends rimonabant if orlistat and sibutramine are contraindicated or no response is

seen. Orlistat is an inhibitor of pancreatic and gastrointestinal lipases, preventing the

absorption of dietary fat. As such, the gastrointestinal side effects of diarrhea and oily
stools makes compliance with orlistat an issue. Sibutramine is a serotonin and
noradrenaline reuptake inhibitor and its side effects include hypertension. Both drugs result
in modest weight loss in clinical trials of between 4 and 8%. Rimonabant is a CB1 receptor
antagonist that acts on several pathways within the brain to reduce weight (see '
Endocannabinoids' section). It is contraindicated in patients with a history of psychiatric
illness. Work is currently underway to identify novel treatments that act within the CNS to
control appetite. MC4-R agonists[122] and drugs that modulate NPY[218,219] and
serotonergic[220] signaling are currently being investigated.[221]

Five-year View
The challenge ahead will be to try and discern how the complex pathways and
neuropeptides within the hypothalamus interact to affect appetite. In addition to
discovering new peptides that influence food intake, the focus will be on modulating known
central pathways using peripherally administered agents. In reality, management of obesity
will be like that of hypertension, requiring lifelong multiple agents in order to achieve the
weight loss required. Delivery of drugs acting centrally will be vital and will need to
overcome barriers, such as the short half-life of peptides, ability to cross the blood-brain
barrier, side effects and safety profile.

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