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

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.[144,145,146] Insulin and leptin levels are also proportional to fat mass and have profound effects on appetite.

Leptin is secreted by adipocytes and circulates at concentrations proportional to fat mass. Rodents and humans lacking leptin (ob/ob mice)[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 monophosphate-activated 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]

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]

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