SUN-022 Absence of Neuronal Androgen Receptor (AR) Improves Glucose Homeostasis in Female Mice

Androgen excess predisposes females to type 2 diabetes (1). Using mouse models of testosterone excess, we reported that this is due, at least partially, to excess AR activation in pancreatic β-cells and neurons. Excess AR activation in β-cells causes β-cell dysfunction while excess AR activation in neurons causes peripheral insulin resistance (2). However, the role of neuronal AR in insulin sensitivity and glucose homeostasis in female mice under physiological testosterone levels is unknown. To address this issue, we used Cre-lox technology to generate female mice with neuronal androgen receptor knockout (NARKO). We explored the role of neuronal AR in glucose homeostasis in NARKO and littermate control female mice challenged with a western diet high in fat and sugars. At 2 months of age, female NARKO mice exhibited similar glucose homeostasis to that of control littermates. However, starting at 4 months of age, female NARKO mice developed improved glucose homeostasis. Compared to control littermates, female NARKO mice exhibited decreased glucose and insulin levels in the fasting state and following a glucose challenge. This phenotype became more pronounced at 6 and 8 months of age. These results suggest that the absence of AR signaling in neurons protects female mice challenged with nutrient excess from the development of insulin resistance and type 2 diabetes. Further studies are needed to determine the mechanism through which absence of neuronal AR protects female mice from insulin resistance. References: (1) Morford et al., Mol Cell Endocrinol. 2018;465:92-102. (2) Navarro et al., JCI Insight. 2018;3(12):e98607. Sources of Research Support: NIH grants R01 DK074970, DK107444, and P50 HD044405 Department of Veterans Affairs Merit Review Award #BX003725