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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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Keep Your Weight In Check During The Holidays

Keep Your Weight In Check During The Holidays

A time for giving and receiving, getting closer with the ones we love and marking the end of another year and all the eating also. We eat because the food is yummy and plentiful but we don't usually count calories at this time of year. This book will help you do just this.

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