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.
Marsh
Donald J
DJ
Department of Obesity Research, Animal Pharmacology, and Comparative Medicine, Merck Research Laboratories, Rahway, NJ 07065, USA. donald_marsh@merck.com
Weingarth
Drew T
DT
Novi
Dawn E
DE
Chen
Howard Y
HY
Trumbauer
Myrna E
ME
Chen
Airu S
AS
Guan
Xiao-Ming
XM
Jiang
Michael M
MM
Feng
Yue
Y
Camacho
Ramon E
RE
Shen
Zhu
Z
Frazier
Easter G
EG
Yu
Hong
H
Metzger
Joseph M
JM
Kuca
Stephanie J
SJ
Shearman
Lauren P
LP
Gopal-Truter
Shobhna
S
MacNeil
Douglas J
DJ
Strack
Alison M
AM
MacIntyre
D Euan
DE
Van der Ploeg
Lex H T
LH
Qian
Su
S
D054369:Agouti-Related Protein; D000818:Animals; D019167:Appetite Stimulants / Q000008:administration & dosage; D001823:Body Composition; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D004041:Dietary Fats / Q000009:adverse effects; D004435:Eating; D004734:Energy Metabolism; D005260:Female; D015870:Gene Expression; D006128:Growth; D006948:Hyperkinesis / Q000209:etiology / Q000378:metabolism*; D006963:Hyperphagia / Q000209:etiology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009478:Neuropeptide Y / Q000008:administration & dosage; D009490:Neurosecretory Systems; D009765:Obesity / Q000139:chemically induced; D010446:Peptide Fragments / Q000008:administration & dosage; D011979:Receptors, Pituitary Hormone / Q000235:genetics / Q000502:physiology*
D054369:Agouti-Related Protein; D019167:Appetite Stimulants; D004041:Dietary Fats; D009478:Neuropeptide Y; D010446:Peptide Fragments; D011979:Receptors, Pituitary Hormone; C411703:agouti-related protein-(83-132); C092274:melanin-concentrating hormone receptor; D003346:Corticotropin-Releasing Hormone