Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance

Several lines of investigation suggest that the hypothalamic neuropeptide m elanin-concentrating hormone (MCH) regulates body weight in mammals. Obese mice lacking functional leptin overexpress the MCH message in the fed or fa sted state. Acute intracerebroventricular injection of MCH increases energy intake in rats. Mice lacking the MCH gene are lean. To test the hypothesis that chronic overexpression of MCH in mice causes obesity we produced tran sgenic mice that overexpress MCH (MCH-OE) in the lateral hypothalamus at ap proximately twofold higher levels than normal mice. On the FVB genetic back ground, homozygous transgenic animals fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wild-type animals, and they had hi gher systemic leptin levels. Blood glucose levels were higher both preprand ially and after an intraperitoneal glucose injection. MCH-OE animals were i nsulin-resistant, as demonstrated by markedly higher plasma insulin levels and a blunted response to insulin; MCH-OE animals had only a 5% decrease in blood glucose after insulin administration, compared with a 31% decrease i n wild-type animals. MCH-OE animals also exhibited a twofold increase in is let size. To evaluate the contribution of genetic background to the predisp osition to obesity seen in MCH-OE mice, the transgene was bred onto the C57 BL/6J background. Heterozygote C57BL/6J mice expressing the transgene showe d increased body weight on a standard diet, confirming that MCH overexpress ion can lead to obesity.