Direct Insulin and Leptin Action on Pro-opiomelanocortin Neurons Is Required for Normal Glucose Homeostasis and Fertility

SummaryCirculating leptin and insulin convey information regarding energy stores to the central nervous system, particularly the hypothalamus. Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy balance and glucose homeostasis and express leptin and insulin receptors. However, the physiological significance of concomitant leptin and insulin action on POMC neurons remains to be established. Here, we show that mice lacking both leptin and insulin receptors in POMC neurons (Pomc-Cre, Leprflox/flox IRflox/flox mice) display systemic insulin resistance, which is distinct from the single deletion of either receptor. In addition, Pomc-Cre, Leprflox/flox IRflox/flox female mice display elevated serum testosterone levels and ovarian abnormalities, resulting in reduced fertility. We conclude that direct action of insulin and leptin on POMC neurons is required to maintain normal glucose homeostasis and reproductive function.

► Redundant glucose regulation is exerted by subpopulations of POMC neurons
► Leptin- and insulin-sensitive POMC neurons control hepatic glucose production
► Leptin and insulin lead POMC neurons to increase energy use and fat storage, respectively
► Subfertility results from ovarian defects linked to high insulin and androgen levels