SUN-485 Investigating the Metabolic and Reproductive Role of AR in Leptin Receptor Expressing Cells

Abstract

Androgens are important for reproductive and metabolic physiology of males and females. Androgens can act upon androgen receptors (AR), which are expressed in many tissues. In the brain, AR is abundant in hypothalamic nuclei involved in the regulation of reproduction and metabolism. While previous studies have examined the contribution of estrogens or estrogen receptors, the role of androgens acting on AR on the central regulation of reproduction and metabolism is less well understood. We have developed an in situ hybridization probe to target AR mRNA in mice. Our preliminary studies have shown that AR is abundant in hypothalamic nuclei, including the arcuate and ventral premammillary nucleus, and is expressed in key neuronal populations associated with the neuroendocrine reproductive axis and the metabolic control of reproduction. One of these neuronal populations expresses the leptin receptor (LepR). The adipocyte secreted hormone leptin signals energy stores to the hypothalamic-pituitary-gonadal axis. Both humans and mice with lack of leptin or LepR are obese, remain in a pre-pubertal state, and are infertile. LepR are highly enriched in the hypothalamus, including areas associated with regulation of reproduction and metabolism. Our hypotheses are that AR expression in LepR cells is necessary for reproduction and metabolism, and that androgens acting on AR in LepR cells mediate the pathophysiology of PCOS. To test our hypothesis, we have generated a genetic mouse model to delete AR from LepR expressing cells (LepRARKO). Our findings show that pubertal timing, estrous cycles, fertility, body weight, and glucose homoestasis do not change in female LepRARKO mice. Male LepRARKO mice show no difference in pubertal timing, fertility, body weight or glucose homeostasis, yet show an increase in spontaneous ambulatory activity during the light phase. Since androgens provide negative feedback to the HPG axis, we investigated whether loss of AR from LepR neurons resulted in changes in gonadotropin levels with gonadectomy. Male LepRARKO mice that were orchidectomized (ORX) show an exaggerated increase in serum LH compared to ORX control males, while FSH and testosterone levels were not significantly different. Completion of our studies will further expand our knowledge of the role that androgens acting on AR play in reproductive and metabolic physiology of males and females.