As a central integrator of energy homeostasis, the hypothalamus also is a source of neuropeptides that inhibit food intake or induce satiety. The hypothalamic anorexi-genic agents include the melanocortins, cocaine- and amphetamine-regulated transcript (CART), and serotonin.
The melanocortins are derived from site-specific, posttranslational cleavage of the precursor parent molecule proopiomelanocortin (POMC). Cleavage of POMC within the anterior pituitary gives rise to Adrenocorticotrophic hormone (ACTH), which acts through the MC2 receptor to stimulate adrenal steroidogenesis. Elsewhere in the brain, POMC is cleaved to another melanocortin, alpha-MSH, which is an agonist for the MC3 and MC4 receptors. Administration of alpha-MSH (i.c.v.) in rodents results in weight loss through inhibition of food intake and stimulation of energy expenditure (22). These actions are mediated through activation of two neuronal melanocortin receptor subtypes (MC3r and MC4r) and antagonized by an adjacent subset of hypothalamic neurons that express AgRP and NPY. The NPY/AgRP neurons that inhibit MC3r and MC4r are themselves inhibited by leptin and insulin.
The integrated physiology of the interactions of these opposing neuropeptides is evident from their weight-related alterations. Following weight loss, the deceasing levels of insulin and leptin lead to activation of NPY/AgRP neurons and inhibition of POMC neurons (23). These counterregulatory changes induce accelerated food intake and accumulation of fat. Defects along the melanocortin signaling pathway, such as those seen in transgenic mice with targeted disruption of the MC4 receptor (knock-outs), result in hyperphagic and massive obesity (24). Recently, fairly widespread functional mutations of the human MC4 receptor have been demonstrated in patients with severe childhood obesity (25) and also linked to binge-eating disorder (26). It should be noted, however, that the majority of obese patients have no demonstrable mutations in MC4, yet such persons may possibly benefit from future therapies targeting activation of MC4 pathways. Indeed, intransal administration of a melanocortin fragment (MSH/ACTH 4_10) looks promising in that regard by inducing modest weight loss (27).
Cocaine- and amphetamine-regulated transcript (CART) is widely expressed in the brain, especially in the hypothalamic nuclei and in the anterior pituitary. Within the arcuate nucleus, POMC colocalizes to neurons that also express CART. Injection of CART (1-100 pmol, i.c.v.) resulted in dose-dependent inhibition of food intake in rats. The effect was observed within 20 minutes and lasted approximately four hours. The decrease in food intake following treatment with CART was accompanied by inhibition of gastric emptying and reduction of oxygen consumption. The arcuate POMC/CART neurons act as downstream effectors of the anorexigenic action of leptin and are markedly stimulated by i.c.v. injection of leptin (28). Interactions between CART and the endogenous opioid, serotononergic (29), and cannabinoid (30) systems provide additional mechanisms for the anorexigenic effects of CART.
The amino acid derivative 5-hydroxytryptamine (serotonin, 5-HT) has ubiquitous neurotransmitter functions on numerous central nervous system (CNS) targets (31). Receptors for 5-HT are widely expressed in regions, including the limbic system, Raphe nucleus, and the hypothalamus. Activation of 5-HT receptors (especially the 5-HT2C subtype) is associated with inhibition of food intake. A similar anorexigenic effect is observed following augmentation of serotonin abundance through inhibition of its reuptake. Studies in rodents have shown that deletion of the serotonin 5-HT2C gene results in marked hyperphagia (32). Unfortunately, clinical experience with selective serotonin reuptake inhibitors shows only modest and inconsistent effects on body weight, indicating that the serotoninergic pathway is overridden by more powerful orexigenic impulses under normal physiological conditions. The major central neuropeptides that impact food intake are summarized in Table 1.1.
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