Targeted disruption of GPR7, the endogenous receptor for neuropeptides B and W, leads to metabolic defects and adult-onset obesity.
Gold-thioglucose (GTG) induces lesions in the ventromedial nucleus of the hypothalamus, resulting in hyperphagia and obesity. To identify genes involved in the hypothalamic regulation of energy homeostasis, we used a screen for genes that are dysregulated in GTG-induced obese mice. We found that GPR7, the endogenous G protein-coupled receptor for the recently identified ligands neuropeptide B and neuropeptide W, was down-regulated in hypothalamus after GTG treatment. Here we show that male GPR7-/- mice develop an adult-onset obese phenotype that progressively worsens with age and was greatly exacerbated when animals are fed a high-fat diet. GPR7-/- male mice were hyperphagic and had decreased energy expenditure and locomotor activity. Plasma levels of glucose, leptin, and insulin were also elevated in these mice. GPR7-/- male mice had decreased hypothalamic neuropeptide Y RNA levels and increased proopiomelanocortin RNA levels, a set of effects opposite to those evident in ob/ob mice. Furthermore, ob/ob GPR7-/- and Ay/a GPR7-/- double mutant male mice had an increased body weight compared with normal ob/ob or Ay/a male mice, suggesting that the obesity of GPR7-/- mice is independent of leptin and melanocortin signaling. Female mice did not show any significant weight increase or associated metabolic defects. These data suggest a potential role for GPR7 and its endogenous ligands, neuropeptide B and neuropeptide W, in regulating energy homeostasis independent of leptin and melanocortin signaling in a sexually dimorphic manner.
Ishii
Makoto
M
Laboratory of Molecular Genetics, The Rockefeller University, New York, NY 10021, USA.
Fei
Hong
H
Friedman
Jeffrey M
JM
D000818:Animals; D001823:Body Composition; D001835:Body Weight; D004435:Eating; D004734:Energy Metabolism; D005260:Female; D007031:Hypothalamus / Q000737:chemistry; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009043:Motor Activity; D009765:Obesity / Q000209:etiology*; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000032:analysis / Q000502:physiology*
C485721:Npbwr1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide