Leptin action via hypothalamic nitric oxide synthase-1 neurons controls energy balance

Few effective measures exist to combat the worldwide obesity epidemic(1), 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 function(2–4). The modest contributions to energy balance attributable to leptin action via many previously-studied LepR-b populations(5–9) 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-b(NOS1)) neurons that comprise approximately 20% of hypothalamic LepR-b neurons. Nos1(cre)-mediated ablation of LepR-b (Lepr(NOS1KO) mice) produces hyperphagic obesity, decreased energy expenditure and hyperglycemia approaching that of LepR-b-null mice. In contrast, endocrine functions in Lepr(NOS1KO) mice are relatively spared. Thus, hypothalamic LepR-b(NOS1) neurons are essential for the control of energy balance by leptin.