Anabolic Effector Systems

Neuropeptide Y

Neuropeptide Y (NPY) is one of the most potent stimulators of food intake (115-117), and is proposed to be an anabolic effector that induces positive energy balance. NPY is a highly expressed peptide in the mammalian CNS (118,119), and is well conserved across species. Hypothalamic NPY neurons are found primarily in the arcuate (ARC) and dorsomedial nuclei, and in neurons such as the PVN (120-125). Endogenous release of NPY is regulated by energy balance. Specifically, in the ARC, food deprivation, food restriction, or exercise-induced negative energy balance each results in upregulation of NPY mRNA in the ARC and increased NPY protein. Repeated administration of NPY results in sustained hyperphagia and rapid body weight gain (126,127). The response of the NPY system to negative energy balance is mediated, at least in part, by the falls in both insulin and leptin that accompany negative energy balance. Central insulin or central/peripheral leptin infusion attentuates the effect of negative energy balance and reduced NPY mRNA levels in the ARC (128-131).

The ARC NPY system has received the most experimental attention; however, there is also evidence that implicates the dorsal medial hypothalamus (DMH) NPY system in the regulation of food intake. The role of NPY in the DMH in regulation of body weight is most evident in several genetic murine obesity models, such as in tubby and agouti lethal yellow mice, where these animals are hyperphagic, yet have no elevations in ARC NPY mRNA, but do have elevations in DMH NPY mRNA (132-134). Rats that do not make a specific receptor for the classic gut-satiety factor, CCK, have elevated body fat mass (135), with elevated NPY mRNA in the DMH but not the ARC. There is growing evidence that points to the hypothesis that there are multiple inputs that determine NPY activity in both the ARC and DMH.

There has been considerable controversy about the importance of the NPY system because mice with a targeted deletion of the NPY gene do not show a dramatic phenotype in terms of their regulation of energy balance (136). Interestingly, when NPY-deficient mice are crossed with obese ob/ob mice, the resultant mice with both NPY and leptin deficiency weigh less than ob/ob mice that have an intact NPY system, indicating that the NPY system contributes significantly to the obesity of ob/ob mice (137). This is consistent with data showing elevated NPY levels in the hypothalamus of ob/ob mice. However, a number of other murine models of obesity have no apparent difference when crossed with NPY-deficient mice (138). Thus one conclusion that could be reached from experiments on NPY-deficient mice suggests that NPY's importance may not be as great as the physiological evidence has indicated. Alternatively, NPY-deficient mice may compensate for developing in the absence of NPY signaling (139,140).

A recent report has further demonstrated the critical role of NPY neurons in the arcuate nucleus. Bruning and colleagues induced targeted expression of a toxin receptor to neurons expressing agouti-related protein (AgRP) (141). NPY and AgRP (discussed in Melanocortin section) are coexpressed in a subset of arcuate nuclei. These are the critical NPY/AgRP neurons that are believed to mediate many of the effects of leptin and insulin on food intake. Using this technique, the investigators were able to induce cell death specifically in these neurons in a temporal manner (141). In contrast to the embryonic deletion of the neurons, mice with adult targeted deletion of the NPY/AgRP neurons stopped eating and lost significant amounts of body adiposity. Indeed, the embryonic ablation of these neurons is consistent with ablation of the individual NPY and AgRP neuropeptides. This elegant study confirms the important role of these cells in the normal regulation of energy balance. Although they are compelling, the data point to the importance of the neurons, not the unique neuropeptides NPY and AgRP (141).

There are several NPY receptors that are critical for the physiological effects observed following NPY administration. Both the Y1 and Y5 receptors have significant expression in areas of the hypothalamus that are sensitive to the orexigenic effects of NPY. However, both pharmacological (142-147) and transgenic approaches to assessing the relative contributions of Y1 and Y5 receptors have resulted in conflicting data. There remains some speculation for the existence of an unidentified NPY receptor that contributes significantly to the feeding response (148). Over the years, the NPY receptors have attracted a significant interest by the biotechnology and pharmaceutical industries (149). Despite this industry investment, NPY antagonists have failed to show significant effi cacy in preclinical obesity models (150). Therefore, it is unlikely that we will see NPY pharmacological agents in the clinic in the near future.

Melanin-Concentrating Hormone

As previously described, the LHA was known as an area critical for the regulation of food intake and fluid intake and was first reviewed in Stellar's original papers in the 1940s and 1950s. There are at least two peptides released from the LHA that appear to mediate these effects: melanin-concentrating hormone (MCH) and orexin (see "Hypocretin/Orexin"). MCH regulates food intake and its expression is increased in obese ob/ob mice (151). When MCH is delivered into the ventricular system it potently increases food intake (152,153) and water intake (154). Unlike NPY, repeated administration of MCH does not result in increased body weight (155). Importantly, mice with targeted deletion of MCH have reduced food intake and decreased body weight and adiposity (156), unlike the NPY-null mice. Recent evidence indicates that MCH is potently regulated by estrogen and may be an important component of mediating the effects of estrogen on food intake and energy balance (157). Because there are MCH projections and receptors that are broadly distributed throughout the neuraxis, and combined with the fact that the MCH knockout animal is lean, it is likely that MCH has a significant role in the regulation of food intake. Several MCH antagonists have been described in the literature and all appear to reduce body weight, food intake, and fat mass (158,159). Indeed, several pharmaceutical companies have begun evaluation of MCH-selective antagonists in humans (160).

Hypocretin/Orexin

"Hypocretins" (161) and "orexins" (162) are two names given to the same peptide. Hypocretin is the more commonly used term in sleep/wake cycle research, whereas orexin is more commonly used in food intake research. The orexins consist of two peptides (ORX-A and ORX-B) and two receptors, and although the cell bodies are located in close proximity to MCH-expressing neurons in the LHA, the two systems do not colocalize to any significant extent (163). Considerable evidence indicates that central administration of ORX-A increases food intake (164,165). Like MCH, orexins have a broad distribution pattern and a variety of evidence links the ORX system directly to the control of arousal (166,167).

In further support of the CNS being an integrated system, the LHA is positioned to receive information about nutrients and information concerning the levels of adiposity signals that are transmitted to the LHA via projections from the ARC. There are significant hypothalamic connections among the ARC, the PVN, and the LHA. Projections from the ARC synapse on both MCH and ORX neurons in the LHA (168). NPY and melanocortin neurons from the ARC interact in a specific way with MCH and the ORX systems in the LHA (164,165,169,170), suggesting that it is tied to energy homeostasis. Additionally, ORX mRNA in the LHA is inhibited by leptin (162) and increased by decreased glucose utilization (171).

Ghrelin

Ghrelin is the endogenous ligand for the growth hormone secretagog receptor (172,173). Endocrine cells of the stomach secrete ghrelin, and consistent with its role as an anabolic effector, centrally and peripherally administered ghrelin results in increased food intake in both rats (174,175) and humans (176). Ghrelin infusion results in dramatic obesity, and circulating ghrelin levels are increased during fasting and rapidly decline after nutrients are provided to the stomach (172,173; for review, see ref. 177). Ghrelin binds to the growth hormone secretagog receptor, which is found in the arcuate nucleus of the hypothalamus. NPY-producing cells in the ARC are critical mediators of the effect of ghrelin (178-181). Finally, clinical evidence points to elevated levels of ghrelin in weight-reduced patients (182) with the notable exception of patients who have been successfully treated for obesity by gastric bypass, in whom circulating ghrelin levels are close to undetectable (183).

As previously discussed, there are numerous peptides secreted from the stomach and intestines that influence food intake. Gastrointestinal signals are thought to be released to restrain the consumption of excess calories and to minimize the increase of postprandial blood glucose (34). Gastrointestinal signals reduce meal size and provide signals as to the complexity of macronutrients consumed. The fact that only one gastrointestinal peptide stimulates food intake speaks to the importance of limiting meal size. The ghrelin signaling pathway has received much publicity in the media and attention by pharmaceutical companies (184). The data suggest that ghrelin antagonists may be potent inhibitors of food intake and good weight loss agents (185). Indeed, several studies indicate that antagonists may be potent food intake inhibitors in lean rodents, though evidence in high-fat-fed diet-induced obese rodents is lacking (186).

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