Project III: Estrogen Receptors and Metabolic Features of PCOS
Polycystic ovary syndrome (PCOS) metabolic dysfunction commonly involves obesity, insulin resistance (IR) and hyperinsulinemia leading to type 2 diabetes mellitus (T2DM). Studies in rodents, sheep, and monkeys repeatedly demonstrate that prenatal or postnatal androgen excess program development of PCOS metabolic dysfunction. Many of these same PCOS features develop in estrogen- or estrogen receptor alpha (ERα)-deficient rodents, specifically following ERα ablation in the hypothalamic ventromedial nucleus (VMN). Prenatal androgen exposure, moreover, induces resistance to many of the actions of estradiol (E2) on gene expression and neuronal activation in mediobasal hypothalamic (MBH) neurons. We therefore hypothesize that such developmental programming of PCOS metabolic features arises from resistance to the actions of E2 in specific hypothalamic neurons. In women and nonhuman primates, however, the specific mechanisms by which E2 regulates energy homeostasis in the hypothalamus remain largely unknown, and the ability of androgens to program altered hypothalamic E2 responsiveness remains untested. These questions will be addressed for the first time in a female nonhuman primate (NHP) through experiments described in the following Specific Aims. We will utilize the common marmoset, Callithrix jacchus, as an experimental model, since serum E2 concentrations are positively associated with improved insulin action in this species, as also shown in cynomolgus macaques. In addition, the marmoset’s relatively rapid development, greater availability, and reduced cost will make these mechanistic studies feasible in a primate, where little is currently known of estrogen-mediated neuroendocrine regulation of metabolic function. All monkeys will be maintained on an obesogenic diet, i.e. in a continued state of positive energy balance, an environment in which estrogens are particularly potent in protecting against weight gain and the development of metabolic dysfunction.
Jon E. Levine, PhD
Professor of Neuroscience and Director, Wisconsin National Primate Research Center, University of Wisconsin-Madison