Hypothalamic Neuropeptides That Stimulate Food Intake

The hypothalamic orexigenic signals include neuropeptide Y (NPY), agouti-related protein (AgRP), and the hypocretins/orexins.

A. Neuropeptide Y

NPY, a 36-amino-acid, COOH-terminally amidated polypeptide first isolated from porcine brain, has structural analogy with peptide YY and pancreatic polypeptide (6). NPY rapidly stimulates food intake following intracerebroventricular (i.c.v.) injection in rodents. The appetite-stimulating effects of NPY lead to sustained hyperphagia and weight gain in mice receiving chronic i.c.v. administration. The specificity of NPY's effect has been established in studies that employed coadministration NPY antagonists or its antibodies, both of which inhibited food intake in rats (7). The role of NPY as a central physiological trigger of meal initiation is suggested by studies showing a rapid increase in hypothalamic NPY expression in the PVN before meal times and persistence of NPY gene expression throughout the period of enforced hunger. The orexigenic action of NPY is mediated by interaction with Y1 and Y5 receptors (8).

Interestingly, NPY expression in the arcuate nucleus is potently antagonized by the anorexigenic hormone leptin. Furthermore, activation of the Y2 receptor subtype on NPY neurons triggers inhibitory presynaptic signals. Central administration of PYY3-36 (a Y2 receptor agonist secreted by intestinal endocrine L cells) into the arcuate elicits a marked inhibition of food intake. Also, Y2 receptor knock-out mice lose their responsiveness to the anorectic effect of PYY3-36 (9). Thus, NPY antagonism appears to be a rather promising potential strategy for antiobesity drug development. The location of the median eminence outside the blood-brain barrier suggests that novel compounds that inhibit NPY gene expression, secretion, or interaction with Y1 and Y5 receptors could possibly be delivered to the hypothalamus when administered systemically.

B. Agouti-Related Protein

AgRP is expressed exclusively in the arcuate nucleus of the hypothalamus and colocalizes to the same neurons that secrete NPY (10). Several reports have confirmed the status of AgRP as a potent orexigenic factor: A single i.c.v. injection of AgRP increases food intake for several days in rodents (11). In contrast to the shortlived effect of NPY, chronic treatment with AgRP leads to sustained hyperphagia and obesity (12). The orexigenic effect of AgRP is mediated through antagonism of MC3 and MC4 receptors. Such antagonism effectively reverses the inhibition of food intake induced by alpha-MSH. The arcuate neurones that cosecrete NPY/AgRP are potently inhibited by leptin and insulin, and activated by ghrelin (8, 13).

C. Hypocretins/Orexins

The hypothalamic peptides hypocretin-1 and hypocretin-2 were discovered in 1998 by subtractive polymerase chain reaction (14). In the same year, homologous hypothalamic peptides named orexins 1 and 2 were discovered by Sakurai et al. (15) and were shown to potently stimulate food intake in rats (15). The hypocretins/orexins stimulate food intake in rodents, an effect that is blocked by neutralizing antibodies to endogenous hypocretins (17).

In addition to directly stimulating food intake, the hypocretins/orexins may also influence energy homeostasis in other ways. For example, hypocretin levels increase in response to exercise, neuroglycopenia, and enforced wakefulness (16). Hypocre-tin-secreting neurons localize exclusively to the lateral hypothalamus, the region of the brain long known to integrate appetite signals. Although intriguing as modulators of food intake, interest in the hypocretins/orexins shifted to their role in sleep regulation when the genes for hypocretins/orexins were found to be the loci for narcolepsy (18, 19). Documented mutations in the human hypocretin/orexin genes are rare among patients with sleep disorders, but nearly 90 percent of patients with narcolepsy-cataplexy have subnormal cerebrospinal fluid hypocretin levels (20).

The latter finding is inconsistent with a primary orexigenic role of the hypocre-tins/orexins as the mechanism for the increased prevalence of obesity, insulin resistance, and type 2 diabetes among patients with narcolepsy (Nishino 2001b). These metabolic disorders are more likely the result of the physical hypoactivity associated with narcolepsy. It must be noted, however, that the hypocretin/orexin system functions centrally as the major integrator of excitatory impulses from monoaminergic (dopamine, norepinephrine, serotonin, histamine) and cholinergic fibers that maintain wakefulness and vigilance (21). Thus, besides a direct orexigenic effect, the hypocretins/orexins could exert metabolic effects through modulation of central autonomic outflow. However, the hypocretins/orexins are less attractive candidates for drug development because their reported effects on food intake are less robust and consistent compared with the orexigenic effects of NPY.

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