Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity.
The hypothalamic neuropeptide melanin-concentrating hormone (MCH) has been implicated in a variety of physiological functions including the regulation of feeding and energy homeostasis. Two MCH receptors (MCHR1 and MCHR2) have been identified so far. To decipher the functional role of the MCH receptors, we have generated and phenotypically characterized mice rendered deficient in MCHR1 expression by homologous recombination. Inactivation of MCHR1 results in mice (MCHR1-/-) that are resistant to diet-induced obesity. With a high-fat diet, body fat mass is significantly lower in both male (4.7 +/- 0.6 g vs. 9.6 +/- 1.2 g) and female (3.9 +/- 0.2 vs. 5.8 +/- 0.5 g) MCHR1-/- mice than that of the wild-type control (P < 0.01), but the lean mass remains constant. When normalized to body weight, female mice are hyperphagic, and male mice are hyperphagic and hypermetabolic, compared with wild-type mice. Consistent with the lower fat mass, both leptin and insulin levels are significantly lower in male MCHR1-/- mice than in the wild-type controls. Our data firmly establish MCHR1 as a mediator of MCH effects on energy homeostasis and suggest that inactivation of MCHR1 alone is capable to counterbalance obesity induced by a high-fat diet.
Chen
Yanyun
Y
Division of Endocrinology, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285, USA.
Hu
Changzhi
C
Hsu
Chiun-Kang
CK
Zhang
Qing
Q
Bi
Chen
C
Asnicar
Mark
M
Hsiung
Hansen M
HM
Fox
Niles
N
Slieker
Lawrence J
LJ
Yang
Derek D
DD
Heiman
Mark L
ML
Shi
Yuguang
Y
D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects / Q000235:genetics; D015152:Blotting, Northern; D015139:Blotting, Southern; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D002153:Calorimetry, Indirect; D018076:DNA, Complementary / Q000235:genetics; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005260:Female; D005838:Genotype; D006963:Hyperphagia / Q000235:genetics* / Q000523:psychology*; D007028:Hypothalamic Hormones / Q000502:physiology*; D008297:Male; D008543:Melanins / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology; D010907:Pituitary Hormones / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D011979:Receptors, Pituitary Hormone / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics
D018076:DNA, Complementary; D004041:Dietary Fats; D007028:Hypothalamic Hormones; D008543:Melanins; D010907:Pituitary Hormones; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; C019463:melanin-concentrating hormone