Abstract
GPR88 is an orphan G-protein-coupled receptor with predominant expression in reward-related areas in the brain. While the lack of GPR88 has been demonstrated to induce behavioral deficits, the potential function of the receptor in the control of food intake and energy balance remains unexplored. In this work, the role of GPR88 in energy homeostasis was investigated in Gpr88−/− mice fed either standard chow or high fat diet (HFD). Gpr88−/− mice showed significantly reduced adiposity accompanied with suppressed spontaneous food intake, particularly pronounced under HFD treatment. While energy expenditure was likewise lower in Gpr88−/− mice, body weight gain remained unchanged. Furthermore, deregulation in glucose tolerance and insulin responsiveness in response to HFD was attenuated in Gpr88−/− mice. On the molecular level, distinct changes in the hypothalamic mRNA levels of cocaine-and amphetamine-regulated transcript (Cartpt), a neuropeptide involved in the control of feeding and reward, were observed in Gpr88−/− mice. In addition, GPR88 deficiency was associated with altered expressions of the anorectic Pomc and the orexigenic Npy in the arcuate nucleus, especially under HFD condition. Together, our results indicate that GPR88 signalling is not only important for reward processes, but also plays a role in the central regulatory circuits for energy homeostasis.
Highlights
Obesity occurs when chronic increase in energy intake significantly exceeds energy expenditure[1]
While considerable efforts have been made to explore the role of GPR88 in reward and behavioral aspects, our work provides the first evidence that GPR88 influences the regulation of energy homeostasis at various levels
This is clearly demonstrated in mice lacking GPR88, which showed a significant decrease in adiposity associated with marked reduction in daily spontaneous food intake under chow and high fat diet conditions, without any change in body weight gain
Summary
Obesity occurs when chronic increase in energy intake significantly exceeds energy expenditure[1]. Microarray profiling in our Cartpt knockout mouse model[31] revealed that Gpr[88] was amongst the most significantly upregulated GPCR mRNAs in the hypothalamus compared to wild-type mice, despite moderate hypothalamic expression of the receptor[13, 14, 25]. These correlative findings in the two genetic models indicate a potential function for GPR88 in the energy homeostatic circuit. Effects of high fat diets on the manifestation of GPR88 deficiency were addressed in comparison with standard chow feeds to examine the potential influence of Gpr[88] deletion on diet-induced obesity
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