1768-P: the Role of Hypothalamic Growth Hormone Receptor–Expressing Neurons in Glucose Metabolism and Energy Homeostasis

GH and the GH receptor (GHR) are present in regions known to participate in the regulation of feeding, energy balance and glucose metabolism, including the hypothalamus. We have previously demonstrated that GHR signals in nutrient-sensing neurons is critical for hepatic glucose production and lipid metabolism. Given the high expression pattern of GHR in the arcuate nucleus (ARC) of the hypothalamus, we aimed to define the specific role of the ARC GHR-expressing neurons in energy homeostasis and glucose metabolism. For this purpose, we have developed a novel GHR cell-specific molecular tool (GHRcre) using CRISPR/Cas9 gene editing technology. We show that GHR+ neurons in the ARC are mostly co-localized with AgRP, GHRH, and SST neurons and rapidly respond to fasting. Specific chemogenetic activation of GHR+ neurons in the ARC (ARCGHR+) by the DREADDs technique impaired glucose metabolism, suggesting the role of these neurons in metabolic homeostasis. Additionally, while activation of ARCGHR+ neurons increased energy homeostasis (RER, VO2) under metabolic resting phase, the responses to fasting were significantly attenuated, demonstrating the inhibitory role of GHR+ neurons in the ARC for fasting responses. Sirtuin 1 (SIRT1) is highly expressed in the ARC and had been associated with hypothalamic responses to fasting. The majority of ARCGHR+ neurons express SIRT1 and respond to fasting by upregulating the SIRT1 expression. Importantly, hypothalamic upregulation of SIRT1 in response to fasting is blunted in mice lacking GHR in AgRP neurons (AgRPEYFP∆GHR mice), suggesting a novel role of SIRT1 within the hypothalamic GH axis and providing evidence for a link between the somatotropic system and SIRT1 function in responses to fasting. Disclosure J. Lima: None. L.K. Debarba: None. I.T. Ayyar: None. C. Ubah: None. M. Khan: None. H. AlRomdhan: None. M. Alysofi: None. M. Sadagurski: None. Funding American Diabetes Association (1-18-JDF-063 to M.S.); Wayne State University