Targeted disruption of GPR7, the endogenous receptor for neuropeptides B and W, leads to metabolic defects and adult-onset obesity

Abstract

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 ob͞ob mice. Furthermore, ob͞ob GPR7؊͞؊ and Ay͞a GPR7؊͞؊ double mutant male mice had an increased body weight compared with normal ob͞ob or Ay͞a 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.M aintenance of a stable body weight in mammals requires the precise balance of energy input (feeding) and energy output (energy expenditure). The hypothalamus has been identified as a main central regulator controlling energy homeostasis through a complex neuronal circuit involving classical neurotransmitters and a number of neuropeptides (1). Classical studies of animals with hypothalamic lesions have suggested that a ''satiety center'' in the ventromedial hypothalamic nucleus (VMH) can induce a state of negative energy balance and that a ''feeding center'' in the lateral hypothalamic area (LH) can induce a state of positive energy balance (1, 2). Thus, VMH lesions lead to hyperphagia and obesity, and LH lesions cause hypophagia and leanness. VMH lesions can be either electrolytic or chemical, as a single i.p. injection of gold-thioglucose (GTG) selectively ablates neurons in the VMH, causing obesity (3, 4). Evidence suggests that GTG selectively targets glucose responsive neurons in the VMH and induces neurotoxicity specifically because of the gold moiety (5, 6).We set out to test the possibility that genes regulating energy homeostasis can be found by identifying cDNAs whose expression levels differed between GTG-treated and saline-treated control animals. Hypothalamic genes that are ablated or downregulated after GTG treatment could possibly account for some part of the hyperphagic obese syndrome in mice with selective VMH lesions. In our study, we identified one such gene, GPR7, the en...

Neuropeptide W exerts a potent suppressive effect on blood leptin and insulin concentrations in the rat

“…Intracerebroventricular infusion of NPB in mice induced hyperphagia during the first 2 h, followed by hypophagia (8). On the other hand, male NPBWR1 -/-mice developed adultonset obesity (7). NPB-deficient mice also manifested a mild, adult-onset obesity similar to that seen in NPBWR1-null mice (13).…”

“…Intracerebroventricular infusion of NPB or NPW affects food intake and energy expenditure (5,8,(10)(11)(12). Furthermore, targeted disruption of the NPBWR1 gene leads to metabolic defects and adult-onset obesity (7). Similar effects have been observed in NPB-null mice (13).…”

“…This effect may explain the findings of Tanaka et al (8) demonstrating NPB-induced hyperphagia within the first 2 h of the experiment, followed by hypophagia. On the other hand, Ishii et al (7) suggest that obesity in NPBWR1 -/-mice is independent of leptin and melanocortin signaling. These observations of NPBWR1-deficient obese animals, however, provide proof of compensatory mechanisms occurring in such mice.…”

“…The amino acid sequence of NPW23 is identical to the first 23 Nterminal amino acids of NPW30 (4,5). Expression of NPB, NPW and their receptor gene was found to be present in the central nervous system and in the peripheral organs of humans, rats, and mice (1,2,(5)(6)(7)(8)(9). Distribution of the gene expression within the brain suggests that NPB plays a role in the control of feeding and neuroendocrine axis functions, as well as in memory and learning processes.…”

Expression of neuropeptides B and W and their receptors in endocrine glands of the rat

“…In rodents GPR8 is absent, its counterpart being described as GPR8-like receptor (GPR8-LR) (3). NPB, NPW and their receptors are highly expressed in the human and rodent central nervous system (especially hypothalamus) (1)(2)(3)(4)(5)(6)(7)(8), and findings have been accumulated that these peptides are involved in the central regulation of feeding behavior and energy homeostasis (6,(9)(10)(11)(12).…”