Suppression of GHS-R in AgRP neurons mitigates diet-induced obesity by activating thermogenesis

Authors: WU, CHIA-SHAN - Texas A&M University; BONGMBA, ODELIA - Children'S Nutrition Research Center (CNRC); YUE, JING - Children'S Nutrition Research Center (CNRC); LEE, JONG HAN - Children'S Nutrition Research Center (CNRC); LIN, LIGEN - Children'S Nutrition Research Center (CNRC); SAITO, KENJI - Children'S Nutrition Research Center (CNRC); PRADHAN, GEETALI - Children'S Nutrition Research Center (CNRC); LI, DE-PEI - Md Anderson Cancer Center; PAN, HUI-LIN - Md Anderson Cancer Center; XU, ALLISON - University Of California; GUO, SHAODONG - Texas A&M University; XU, YONG - Children'S Nutrition Research Center (CNRC); SUN, YUXIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/7/2017
Publication Date: 4/14/2017
Citation: Wu, C., Bongmba, O., Yue, J., Lee, J., Lin, L., Saito, K., Pradhan, G., Li, D., Pan, H., Xu, A., Guo, S., Xu, Y., Sun, Y. 2017. Suppression of GHS-R in AgRP neurons mitigates diet-induced obesity by activating thermogenesis. International Journal of Molecular Sciences. 18(4):832.

Interpretive Summary: Obesity is a serious global health problem. Ghrelin is a hormone that stimulates food intake and suppress energy expenditure. Here we showed that effects of ghrelin on energy expenditure are mediated through its actions in a brain neuron type, called AgRP neurons. These findings facilitate development of new therapy for weight management.

Technical Abstract: Ghrelin, an orexigenic hormone released primarily from the gut, signals the hypothalamus to stimulate growth hormone release, enhance appetite and promote weight gain. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related Peptide (AgRP) neurons of the hypothalamus. We recently reported that neuron-specific deletion of GHS-R completely prevents diet-induced obesity (DIO) in mice by activating non-shivering thermogenesis. To further decipher the specific neuronal circuits mediating the metabolic effects of GHS-R, we generated AgRP neuron-specific GHS-R knockout mice (AgRP-Cre;Ghsrf/f). Our data showed that GHS-R in AgRP neurons is required for ghrelin's stimulatory effects on growth hormone secretion, acute food intake and adiposity, but not for long-term total food intake. Importantly, deletion of GHS-R in AgRP neurons attenuated diet-induced obesity (DIO) and enhanced cold-resistance in mice fed high fat diet (HFD). The HFD-fed knockout mice showed increased energy expenditure, and exhibited enhanced thermogenic activation in both brown and subcutaneous fat; this implies that GHS-R suppression in AgRP neurons enhances sympathetic outflow. In summary, our results suggest that AgRP neurons are key site for GHS-R mediated thermogenesis, and demonstrate that GHS-R in AgRP neurons plays crucial roles in governing energy utilization and pathogenesis of DIO