Role of Androgen Receptor in Hypothalamic Regulation of Metabolism and Reproduction

Abstract

Androgens are steroid hormones that have sex-specific effects on regulation of metabolic and reproductive physiology. Androgens primarily act upon nuclear hormone receptors, including androgen receptors (AR), or estrogen receptors (ERs) after conversion to estradiol by aromatase. Adult males typically have higher levels of circulating androgens. However, imbalance of androgens outside the homeostatic range has both reproductive and metabolic deficits for both sexes. For example, hypoandrogenism in males and hyperandrogenism in females can result in infertility, obesity, and increased risk of diabetes. While many tissues express AR and are sensitive to the effects of androgens, the brain is a key androgen responsive organ. In adults, AR is expressed in many brain regions, including those that are involved in regulation of reproduction, metabolism, behavior, cognition, mood, and autonomic processes. Yet, characterization of AR expression has been lacking in the female and prepubertal brain. Here, we present a comprehensive neuroanatomical characterization of Ar mRNA expression in the mouse brain of both sexes, and compare adult and prepubertal expression. We found that expression of Ar undergoes dynamic change during a critical window of prepubertal development in male and female mice. Furthermore, we describe brain regions that may preferentially respond to androgens, rather than estrogens. For example, the ventral premammillary nucleus (PMv) shows dense expression of AR-immunoreactivity in both sexes, yet it is relatively low in ERs and aromatase. To identify neuronal populations that are targets of androgen action, we compared areas of dense AR expression, including the PMv and arcuate nucleus (ARH), with known neuronal populations in these nuclei. AR was found to be coexpressed in PMv and ARH leptin receptor (LepRb) neurons, which are crucial in regulation of energy homeostasis and exert permissive effects on fertility. We hypothesized that androgens acting via AR in LepRb cells contribute to the regulation of reproduction and metabolism at the hypothalamic level, and that loss of AR from LepRb cells would disrupt reproductive and metabolic homeostasis. We found that deletion of AR from LepRb cells (LepRbΔAR) results in sex-specific changes in the neuroendocrine reproductive axis, locomotor activity, and body composition. We observed that loss of negative feedback actions of sex steroids induces an exaggerated rise in luteinizing hormone in LepRbΔAR male mice and in follicle stimulating hormone in LepRbΔAR female mice. Furthermore, female LepRbΔAR mice show increased lean mass, while male LepRbΔAR mice display increased ambulatory activity. Subsequently, we tested if deletion of AR from LepRb neurons would protect female mice from hyperandrogenism-induced reproductive deficits. Female mice exposed to androgen excess during late prenatal development exhibit disrupted estrous cycles, infertility, and mild metabolic changes during adulthood. This phenotype replicates many features of polycystic ovary syndrome (PCOS), which is also partly characterized by androgen excess. We found that female mice with deletion of AR in LepRb neurons had improved estrous cycles with prenatal androgenization compared to their AR-intact littermates. Our findings highlight that LepRb neurons represent an important target of androgen action in the brain, and contribute to sex-specific differences in the neuroendocrine reproductive axis and some aspects of metabolic regulation. Furthermore, LepRb neurons may be involved in the pathogenesis of PCOS. These studies further elucidate the specific targets of androgens in the brain, and open the possibility of additional mechanistic study into the physiologic actions of androgens, especially in females.