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The GhsrQ343X allele favors the storage of fat by acting on nutrient partitioning

Abstract : The 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 signaling in vivo, we previously reported that a model with enhanced sensitivity to ghrelin ( Ghsr Q343X mutant 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 comparing Ghsr M/M rats to wild-type littermate rats 1) as freely behaving animals and 2) in feeding and locomotor paradigms. Herein, Ghsr M/M rats 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 libitum fed Ghsr M/M rats consumed and conditioned for sucrose similarly to littermate control rats. In calorie-restricted conditions, Ghsr M/M rats retained food anticipatory activity and maintained better their body weight and glycemia. Importantly, prior to fat accumulation, male Ghsr M/M rats preferentially used carbohydrates as fuel substrate without alterations of energy intake, energy expenditure or physical activity and showed alterations of the GHSR system (i.e. enhanced ratio of GHSR hormones LEAP2:acyl-ghrelin and increased Ghsr expression in the hypothalamus). Overall, the present study provides proof of concept that shifted GHSR signaling can specifically alter nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.
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Submitted on : Tuesday, October 5, 2021 - 1:59:29 PM
Last modification on : Thursday, June 9, 2022 - 11:34:15 AM
Long-term archiving on: : Thursday, January 6, 2022 - 7:17:40 PM


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Candice Marion, Philippe Zizzari, Raphael G P Denis, Rim Hassouna, yacine Chebani, et al.. The GhsrQ343X allele favors the storage of fat by acting on nutrient partitioning. Journal of Endocrinology, BioScientifica, 2021, pp.JOE-20-0576.R2. ⟨10.1530/JOE-20-0576⟩. ⟨inserm-03365851⟩



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