TheGhsrQ343Xallele favors the storage of fat by acting on nutrient partitioning

AbstractThe Growth Hormone Secretagogue Receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor endowed of a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signalingin vivo, we previously reported that a model with enhanced sensitivity to ghrelin (GhsrQ343Xmutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparingGhsrM/Mrats to wild-type littermate rats 1) as freely behaving animals using an automated system to monitor simultaneously energy intake and expenditure, respiratory exchanges and voluntary activity and 2) in feeding and locomotor paradigms. Herein,GhsrM/Mrats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved.Ad libitumfedGhsrM/Mrats consumed and conditioned for sucrose similarly to littermate control rats. In calorie-restricted conditions,GhsrM/Mrats retained food anticipatory activity and maintained better their body weight and glycemia. Finally, prior to fat accumulationGhsrM/Mrats showed shifted fuel preference towards carbohydrates utilization without alterations of energy intake, energy expenditure or physical activity. Overall, the present study provides proof of concept that shifted GHSR signaling can operate a specific alteration in nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.