Hypothalamic Regulation of Appetite

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

Disclosures

Expert Rev Endocrinol Metab. 2008;3(5):577-592. 

In This Article

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 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]

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 c-fos 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.[180,181,182] 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]

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-fos expression in the ARC and its anorectic effects can be blocked through the use of a GLP-1 antagonist.[182] In mice, manganese-enhanced 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 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 receptor-knockout 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 (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, PYY3-36 is relatively selective for the Y2 receptor. Peripheral administration of PYY3-36 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 induces c-fos expression in the ARC and direct injection of PYY3-36 into the ARC inhibits feeding.[198] It has been proposed that PYY3-36 exerts its anorectic effect via the Y2 receptor since this is abolished in Y2 receptor-knockout mice.[198] The Y2 receptor is highly expressed on ARC NPY neurons and PYY3-36 may reduce food intake by inhibiting NPY release via autoinhibitory Y2 receptors. PYY3-36 decreases NPY release and increases α-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 brainstem-hypothalamic 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.

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.[205,206,207] 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.

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