Donald J. Marsh1, Drew T. Weingarth1, Dawn E. Novi1, Howard Y. Chen1, Myrna E. Trumbauer1, Airu S. Chen1, Xiao-Ming Guan1, Michael M. Jiang1, Yue Feng1, Ramon E. Camacho1, Zhu Shen1, Easter G. Frazier1, Hong Yu1, Joseph M. Metzger1, Stephanie J. Kuca1, Lauren P. Shearman1, Shobhna Gopal-Truter1, Douglas J. MacNeil1, Alison M. Strack1, D. Euan MacIntyre1, Lex H.T. Van der Ploeg1, Su Qian1
1Departments of Obesity Research, Animal Pharmacology, and Comparative Medicine, Merck Research Laboratories, Rahway, NJ 07065
Tóm tắt
Melanin-concentrating hormone (MCH) is a cyclic 19-aa hypothalamic neuropeptide derived from a larger prohormone precursor of MCH (Pmch), which also encodes neuropeptide EI (NEI) and neuropeptide GE (NGE). Pmch-deficient (
Pmch
−/−
) mice are lean, hypophagic, and have an increased metabolic rate. Transgenic mice overexpressing
Pmch
are hyperphagic and develop mild obesity. Consequently, MCH has been implicated in the regulation of energy homeostasis. The MCH 1 receptor (MCH1R) is one of two recently identified G protein-coupled receptors believed to be responsible for the actions of MCH. We evaluated the physiological role of MCH1R by generating MCH1R-deficient (
Mch1r
−/−
) mice.
Mch1r
−/−
mice have normal body weights, yet are lean and have reduced fat mass. Surprisingly,
Mch1r
−/−
mice are hyperphagic when maintained on regular chow, and their leanness is a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity,
Mch1r
−/−
mice are less susceptible to diet-induced obesity. Importantly, chronic central infusions of MCH induce hyperphagia and mild obesity in wild-type mice, but not in
Mch1r
−/−
mice. We conclude that MCH1R is a physiologically relevant MCH receptor in mice that plays a role in energy homeostasis through multiple actions on locomotor activity, metabolism, appetite, and neuroendocrine function.
