3037-LB: Androgen Receptor Action in Arcuate Nucleus Impairs Estrogen Insulin-Sensitizing Actions and Insulin Suppression of Hepatic Glucose Production in Female Mice

Introduction and Objective: Hyperandrogenemia increases type 2 diabetes risk in women, but neuronal mechanisms linking androgen to insulin resistance are unknown. We tested if testosterone acts via androgen receptors (AR) in the hypothalamic arcuate nucleus (ARC) using a mouse model. Methods: We generated female ARC-specific AR knockout (ARC-ARKO) and control mice by bilateral AAV-Cre-GFP or AAV-GFP injection into the ARC and exposed them to a Western diet. They received dihydrotestosterone (DHT) or vehicle via pellets. We assessed glucose homeostasis by fasting/fed glucose/insulin tolerance tests, and euglycemic, hyperinsulinemic clamp. Ovariectomized ARC-ARKO and control mice were treated by estradiol (E2) to test E2 insulin sensitizing actions in the presence or absence of DHT. We performed Visium HD spatial transcriptomics reconstruction of ARC neurons/astrocytes. Results: DHT induced fasting hyperglycemia and hyperinsulinemia in controls but not ARC-ARKO mice. DHT produced insulin resistance during clamp by blunting insulin suppression of hepatic glucose production (HGP) in control mice, but not in ARC-ARKO mice. Increased HGP was independent of hepatocyte insulin action and linked to an ARC-autonomic IL6-STAT3 liver axis. The E2 insulin sensitizing action (ITT) was blunted by DHT in control mice but DHT-induced estrogen resistance was absent in ARC-ARKO mice. Spatial transcriptomics of the ARC in these mice revealed that DHT overrides E2-dependent synaptic remodeling and metabolic tuning of ARC KNDy, POMC and AgRP neurons. Conclusion: Androgen excess impairs central insulin and E2 control of HGP in female mice via ARC AR. Disclosure M. Qadir: None. J. Morford: None. W. Xu: None. S. Haque: None. F. Mauvais-Jarvis: None. Funding For FM-J: NIH DK074970, P20GM152305, VA BX005812, For MMFQ: NIH K99DK140067