Blockade of MCH1 receptor signalling ameliorates obesity and related hepatic steatosis in ovariectomized mice.

Melanin-concentrating hormone (MCH) is a cyclic orexigenic neuropeptide predominantly expressed in the lateral hypothalamus. We investigated the roles of MCH1 receptor signalling in ovariectomy (OVX)-induced obesity in female C57BL/6J mice, an animal model of postmenopausal obesity. The effects of blocking signalling via the MCH1 receptor on OVX-induced obesity was investigated by using Mch1r deficient (KO) mice and chronic treatment with a selective MCH1 receptor antagonist. OVX induced body weight gain and increases in the weight of visceral fat and of liver; these effects were attenuated following OVX in Mch1r KO mice. OVX-induced triglyceride (TG) accumulation and elevated expression of lipogenic genes were significantly ameliorated in the liver of Mch1r KO mice. In agreement with these results, chronic i.c.v. infusion of a selective MCH1 receptor antagonist significantly reduced body weight gain, visceral fat and liver weights in OVX mice, and hepatic TG contents and lipogenic gene expression levels were normalized. Our results indicate that MCH1 receptor signalling is involved in the development of fatty liver, as well as obesity, in OVX mice, and suggest a therapeutic potential for MCH1 receptor antagonists in the treatment of obesity and fatty liver.