Investigating the Role of GPR160 in Stress-induced anorexia in a global knockout model

Stress-induced anorexia is an adaptive survival mechanism conserved across many species. Feeding behavior is closely linked to the stress response, as stress directly impacts appetite and energy metabolism. At the core of this response are neurons that produce corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release ACTH, ultimately triggering the secretion of corticosterone from the adrenal glands. The presence of CRH in the hypothalamus—a key brain region involved in regulating feeding—underscores the intricate interaction between stress and metabolic pathways. In the central nervous system, cocaine- and amphetamine-regulated transcript (CART) plays a role in modulating the hypothalamic-pituitary-adrenal (HPA) axis, influencing stress responses. CART-producing neurons innervate CRH neurons in the paraventricular nucleus (PVN), enhancing CRH expression and release, thereby amplifying the stress response pathway. CART regulates feeding behavior, satiety, and metabolic function through its receptor, GPR160. Despite extensive studies in GPR160 knockdown (KD) models, such as our previous work with GPR160 knocked down specifically in CRH neurons in rats, the role of GPR160 in global knockout (KO) models remains unexplored. Investigating feeding and stress behaviors in GPR160 KO animals may provide novel insights into its involvement in meal patterning and stress-related behaviors. In this study, we utilize a GPR160 knockout mouse model to investigate the role of GPR160/CART signaling in meal patterning, HPA axis activation, and stress-induced anorexia. We hypothesize that the global loss of GPR160 will result in alterations to meal structure without significantly affecting overall body weight or food intake, a reduction in HPA axis activation in response to stress, and an attenuation of stress-induced anorexia. To test our hypothesis, we first used the BioDAQ continuous food and water intake monitoring system to assess feeding behaviors in both groups. We measured total food and water intake, as well as meal structure and patterning. Satiation parameters were significantly increased in GPR160 KO mice, while parameters like the rate of food consumption decreased. Despite these differences, overall food consumption remained comparable between WT and GPR160 KO mice. Next, we investigated stress-induced anorexia by subjecting the mice to restraint stress just before lights out. Interestingly, the rate of food consumption increased in stressed GPR160 KO mice compared to their handling controls. Additionally, the overall food consumption of stressed GPR160 KO mice was higher than that of their handling controls. Finally, we examined HPA axis activation following acute stress. Plasma corticosterone levels were measured in response to restraint stress, along with CRH and ACTH mRNA levels in the hypothalamus and pituitary, respectively. We found that corticosterone levels increased in both stressed WT and KO mice compared to their non-stressed littermates; however, no significant differences were observed between WT and GPR160 KO mice. While further studies are needed to fully elucidate the roles of CART and GPR160 in stress responses and feeding behavior, our preliminary findings suggest that this ligand-receptor pair could represent a novel therapeutic target for psychiatric disorders associated with stress-induced eating behaviors. Saint Louis University This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.