Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism

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.

黑素浓集激素（Melanin-concentrating hormone, MCH）是一种源自更大分子量MCH激素原前体（Pmch）的环状19肽下丘脑神经肽，该前体同时编码神经肽EI（NEI）与神经肽GE（NGE）。Pmch基因敲除（Pmch(-/-)）小鼠表现为体瘦、摄食减少及代谢率升高；而过表达Pmch的转基因小鼠则会出现摄食过多并发展为轻度肥胖。据此，MCH被认为参与能量稳态的调控。MCH 1型受体（MCH1R）是目前已确认的两种介导MCH生理功能的G蛋白偶联受体之一。本研究通过构建MCH1R基因敲除（Mch1r(-/-)）小鼠，对其生理功能进行了评估。Mch1r(-/-)小鼠体重正常，但体瘦且脂肪量减少。令人意外的是，普通饲料饲养的Mch1r(-/-)小鼠存在摄食过多的现象，其体瘦表型源于运动亢进与代谢异常。与运动亢进表型一致的是，Mch1r(-/-)小鼠对饮食诱导肥胖的易感性更低。值得注意的是，对野生型小鼠进行慢性中枢MCH输注可诱导其摄食过多与轻度肥胖，但该效应在Mch1r(-/-)小鼠中并未出现。综上，我们认为MCH1R是小鼠体内具有生理功能的MCH受体，其通过调控运动活性、代谢、食欲及神经内分泌功能参与能量稳态的维持。