Potential Therapeutic Indications

Beta Switch Program

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Initial studies showing higher expression of MCH in hypothalami of leptin deficient (Lepob/ob) and hypoleptinemic (fasted) mice, and that i.c.v. administration of MCH to rats stimulates food intake, established a role for MCH in feeding [37]. Several groups have since confirmed the hyperphagic effect of acute central administration of MCH in both mice and rats [38-41], as well as the over-expression of MCH in genetic models of leptin resistance [42,43]. Sub-chronic (7-14 days) central infusion of MCH to mice on a high fat diet induced persistent hyperphagia accompanied by increased adiposity, hyperinsulinemia and hyperleptinemia [44,45]; while i.c.v. infusion of a potent MCH1-R peptide agonist to rats produced similar effects [46]. Consistent with these findings, transgenic eutopic over-expression of MCH produces an obese, insulin resistant and hyperphagic phenotype in mice on a high fat diet [47]. Deletion of the pmch gene, which generates an animal null for MCH as well as NEI and NGE, results in a lean phenotype characterized by hypophagia and increased energy expenditure [48]. MCH1-R null mice are lean, and have decreased leptin and insulin levels, similar to the findings in the pmch-' mice [49,50]. Additionally, they fail to respond to exogenously administered MCH and are resistant to diet-induced obesity. Unlike the MCH deficient mice, however, mchlr-' mice are hyperphagic, and the leanness is due to a hyperactive and hypermetabolic pheno-type. This hyperphagia is not explained by alterations in the expression of ore-xigenic (NPY, AgRP, orexin) and anorexigenic (CART, POMC) neuropeptides, nor in the tone of endogenous orexigenic signals as evidenced by a normal response to exogenously administered AgRP and NPY. Rather, it has recently been shown that the hyperactive phenotype of mchlr'-' mice is associated with an increased heart rate and an altered autonomic regulation of body temperature in response to fasting [51].

Taken as a whole, these studies convincingly demonstrate that MCH signaling plays a pivotal role in the regulation of both food intake and energy expenditure. Several preclinical studies suggest that small molecule MCH1-R antagonists will be efficacious for the treatment of obesity.

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