Leptin action through hypothalamic nitric oxide synthase-1–expressing neurons controls energy balance

Abstract

SummaryFew effective measures exist to combat the worldwide obesity epidemic1, and the identification of potential therapeutic targets requires a deeper understanding of the mechanisms that control energy balance. Leptin, an adipocyte hormone that signals the status of cellular energy stores, acts via multiple types of leptin receptor (LepR-b)-expressing neurons in the brain to control feeding, energy expenditure and endocrine function2–4. The modest contributions to energy balance attributable to leptin action via many previously-studied LepR-b populations5–9 suggest that other, heretofore unidentified, hypothalamic LepR-b neurons play important roles. Here, we examine the role of LepR-b in neuronal nitric oxide synthase (NOS1)-expressing (LepR-bNOS1) neurons that comprise approximately 20% of hypothalamic LepR-b neurons. Nos1cre-mediated ablation of LepR-b (LeprNOS1KO mice) produces hyperphagic obesity, decreased energy expenditure and hyperglycemia approaching that of LepR-b-null mice. In contrast, endocrine functions in LeprNOS1KO mice are relatively spared. Thus, hypothalamic LepR-bNOS1 neurons are essential for the control of energy balance by leptin.