Effects of Cocaine- and Amphetamine-Regulated Transcript (CART)
Cocaine- and amphetamine-regulated transcript (CART) is a recently discovered hypothalamic pept-ide which is regulated by leptin and is endowed with appetite-suppressing activity (69,70). In the rat, the CART gene encodes a peptide of either 129 or 116 amino acid residues (70). In contrast, only the short form of CART exists in humans (70). The mature peptide contains several potential cleavage sites and CART may be post-transcriptionally processed into several biologically active fragments. Thus, in most tissues studied, CART peptides are short, CART (42-89) being found in the rat hypothalamus (71). This tissue processing of CART resulting in neuropeptides of different lengths may indicate that different CART peptides have different biological functions (71).
Acute i.c.v. CART administration to normal rats produces a dose-dependent decrease in food intake (69,72). CART also transiently decreases the NPY-elicited feeding response in normal rats (69). Finally, CART appears to have a tonic inhibitory influence on food intake, as treatment of rats with anti-CART antiserum results in increased food intake (69).
CART is regulated, in part, by leptin as chronic peripheral leptin administration to the leptin-defi-cient ob/ob mice results in a definite augmentation of the low expression of CART measured in the hypothalamic arcuate nucleus of these animals, an increase that is paralleled by the observed decrease in body weight. CART expression is also markedly reduced in the genetically obese leptin-resistant fa/ fa rat, thus possibly playing a role in the hyper-phagia of this animal (69). The physiological and pathological importance of CART has yet to be substantiated, although preliminary results with chronic infusion of the neuropeptide appear to indicate that it markedly reduces food intake and body weight of both normal and obese rats.
Effects of Corticotropin-releasing Hormone (CRH)
Apart from its role as controller of the hy-pothalamo-pituitary-adrenal (HPA) axis, CRH, a 41 amino acid neuropeptide, also functions as a central effector molecule that brings about a state of negative energy balance and weight loss. This is due to the ability of central CRH to decrease food intake (73), to increase the activity of the sympathetic nervous system and to stimulate thermogenesis (73-75). CRH also influences gastrointestinal functions, inhibiting gastric acid secretion and gastric emptying, processes that are controlled by the para-sympathetic nervous system (76-79). Chronic i.c.v. CRH administration in normal (73), genetically obese fa/fa rats (80), as well as in monkeys (81), decreases food intake and body weight, partly by acting on energy dissipating mechanisms. Central microinjections of CRH were shown to inhibit NPY-induced feeding (82), in keeping with the notion that the locally released CRH could restrain the effect of NPY and/or of other orexigenic signals. Leptin administration results in transient increases in hypothalamic CRH levels, thus potentially favoring the CRH effects just mentioned (22). The leptin effect on CRH could occur via its increasing CRH type 2 receptor (CRHR-2) expression in the ven-tromedial hypothalamus, as these receptors are potentially responsible for the CRH-mediated decrease in food intake and sympathetic nervous system activation (83,84).
The Melanocortin System and Effects of a-Melanocyte-stimulating hormone (a-MSH)
Pro-opiomelanocortin (POMC) is the precursor of many different molecules, the melanocortins, among which are ACTH, ^-endorphin, the melanocyte-stimulating hormones (a-,^-,y-MSH). The a-melanocyte-stimulating hormone a-MSH is a 13 amino acid peptide which binds with different affinities to five different subtypes of G-protein-coupled receptors. An involvement of a-MSH in body weight homeostasis via an interaction with the melanocortin-4 (MC4), possibly the MC3 receptors, has been recently described. MC3 receptors are present mainly in the hypothalamus, MC4 receptors throughout the brain and in the sympathetic nervous system (85,86). When administered i.c.v. to normal rats, a-MSH decreases food intake (34), as does the central administration of a stable linear analog of a-MSH, NDP-MSH (87). The relationships existing between the melanocortins, their receptor subtypes and feeding have been illustrated by studying synthetic melanocortin receptor agonists and antagonists, amongst which are the compounds called MTII and SHU9119 (85,88). The i.c.v. administration of the agonist MTII markedly and dose-dependently inhibits food intake, while that of the antagonist SHU9119 markedly and dose-dependently stimulates food intake process (85,89). The co-injection of equal concentrations of the agonist and of the antagonist results in a food intake that is identical to that of control rats (85). In addition, MTII inhibits or suppresses, depending on the dose, the feeding response elicited by neur-opeptide Y (85), in keeping with the observation that both MC3 and MC4 receptors are found in CNS sites in which NPY neurons are also present (90).
The effect of a-MSH in decreasing food intake is under the 'tonic' inhibitory influence from a melanocortin-receptor antagonist called 'agouti-related protein' (AGRP). When an active fragment of AGRP is administered i.c.v. to rats, an increased food intake is observed. Moreover, when a-MSH is similarly administered, the observed decrease in food intake is blocked by the further addition of AGRP (91).
The fundamental importance of the MC4 receptors has been highlighted by obtaining transgenic mice lacking the MC4 receptors (MC4-R-deficient mice). These mice (female and male) exhibit increased food intake and become obese. Both sexes have marked hyperinsulinemia, hyperleptinemia, with either normoglycemia (females) or hyper-glycemia (males), plasma corticosterone levels being normal. These data support the view that MC4 receptors are essential in the cascade of events normally leading to decreased food intake and leanness
(92). The decreased food intake produced by a-MSH and the subsequent cascade of events summarized above is accompanied by a change in the activity of the sympathetic nervous system. Thus, activation of the MC3/MC4-receptor system by the agonist MTII administered centrally results in a marked, specific, dose-dependent activation of the sympathetic nerves innervating the brown adipose tissue, as well as the renal and lumbar beds, while no change in blood pressure or heart rate is observed
(93). The combination of decreased food intake and increased sympathetic activation with likely increase in energy dissipation suggests that the melanocortin system is well adapted to play a role in decreases in body weight.
Since the main central effects of leptin are to decrease food intake and body weight, and to increase energy dissipation, it has been postulated that this hormone could bring about these changes by influencing the melanocortin system. It is thus of interest to observe that the effect of leptin in decreasing food intake is blocked by a MC4 receptor antagonist (SHU9119), and that pretreatment with the antagonist is able to prevent the effects of leptin in decreasing both food intake and body weight. This effect is specific as the antagonist did not affect the decreased food intake produced by another peptide (GLP-1) (94). Thus, the MC4-receptor signaling is important in mediating the effects of leptin. In keeping with this finding is the observation that the MC4 receptor agonist, MTII, which decreases food intake in normal animals, also suppresses the hyperphagia of the leptin-deficient ob/ob mice. This suggests that leptin acts via MC4 receptors and that in the absence of leptin, i.e. in ob/ob mice, the lack of signaling through MC4 receptors would be responsible for the increased food intake (95), a viewpoint that remains to be fully validated (96).
When considering POMC (the precursor of melanocortins, of a-MSH) and AGRP (the antagonist of the MC4 receptor), it is of interest to observe that the lack of leptin in the ob/ob mouse (or lack of leptin signaling in the db/db one) is accompanied by a decrease in POMC expression and an increase in that of AGRP (97—99). Moreover, leptin administration leads to an increase in POMC expression and a decrease in that of AGRP (100—103). It may thus be concluded that leptin decreases food intake and body weight, in part by favoring the action of melanocortin neuropeptide(s) at the MC4 receptor, while concomitantly preventing the inhibitory influence of AGRP on this same receptor, a concept excellently reviewed elsewhere (102). This specific effect of leptin is probably additive to its inhibitory one on hypothalamic NPY levels, NPY being one of the most potent food stimulators as described above, and being co-expressed with AGRP within the arcuate nucleus of the hypothalamus (104).
Obesity, as mentioned above, may result from altered functions of the MC4 receptors. This is illustrated in a global fashion by the observation that when the melanocortin receptor agonist (MTII) is administered i.c.v. to fasted—refed hyperphagic mice, to obese ob/ob mice, to yellow (Ay) obese mice, to NPY hyperphagic mice, their respective hyper-phagia is largely canceled (95). In addition, it has been recently demonstrated that mice lacking POMC (hence lacking subsequent a-MSH synthesis and its inhibitory effect on feeding via its binding to MC4 receptors) overeat and become obese, a situation partly reversed by an a-MSH treatment (105).
The yellow obese mouse is an interesting animal model that underlines the potential importance of the melanocortin system. As reviewed recently, the pigment produced by melanocytes in the skin is under the regulation of a-MSH and a paracrine melanocyte signaling molecule called 'agouti' (from American Spanish 'aguti', meaning alternation of light and dark bands of colors in the fur of various animals). Agouti binds to MC1 receptors and decreases their signaling, resulting in decreased cAMP levels, thereby inducing melanocytes to synthesize a yellow pigment (pheomelanin). a-MSH binds to MC1 receptors and increases their signaling, resulting in increased cAMP, thereby stimulating the synthesis of a black pigment (eumelanin). The classical agouti hair color of many species appears brown, although the 'brown' hairs are in fact black-yellow-
black banded hairs, due to the joint effects of agouti and a-MSH. The yellow mouse (Ay) is heterozygous for a mutation in the agouti gene. This mutation results in an ectopic expression of the agouti protein throughout the body, while the non-mutated gene induces the expression of the agouti protein only in hair follicles. The ectopic expression of agouti is at the origin of many different effects, i.e. yellow hairs, increased linear growth, decreased fertility, obesity. Within the brain, ectopic agouti functions as an antagonist of the MC4 receptor (with little effect on MC3-R), preventing the action of endogenous MC4 receptor agonists, with resulting obesity (102).
From a physiopathological viewpoint, the agouti protein turns out not to be as esoteric as it may sound. Indeed, a pathway very similar to that of the agouti in the skin has been described in the hypothalamus. Moreover, a novel gene called AGRP (agouti-related protein) or ART (agouti-related transcript) has been discovered in the hypothalamus of rodents as well as humans (97,98). It encodes a melanocortin (MC3, MC4) receptor antagonist comprising 132 amino acid residues which, as mentioned above, is the likely natural antagonist of the brain melanocortin system (97,98). The importance of the AGRP pathway is supported by the observation that over-expression of human AGRP in transgenic mice induces obesity without producing a yellow color of the fur, ARGP having no effect on MC1 receptors and therefore on the coat color (97,106).
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