Few effective measures exist to combat the worldwide obesity epidemic, and the identification of potential therapeutic targets requires a deeper understanding of the mechanisms that control energy balance. Leptin, an adipocyte-derived hormone that signals the long-term status of bodily energy stores, acts through multiple types of leptin receptor long isoform (LepRb)-expressing neurons (called here LepRb neurons) in the brain to control feeding, energy expenditure and endocrine function^,,. The modest contributions to energy balance that are attributable to leptin action in many LepRb populations^,,,, suggest that other previously unidentified hypothalamic LepRb neurons have key roles in energy balance. Here we examine the role of LepRb in neuronal nitric oxide synthase (NOS1)-expressing LebRb (LepRb^NOS1) neurons that comprise approximately 20% of the total hypothalamic LepRb neurons. Nos1^cre-mediated genetic ablation of LepRb (Lepr^Nos1KO) in mice produces hyperphagic obesity, decreased energy expenditure and hyperglycemia approaching that seen in whole-body LepRb-null mice. In contrast, the endocrine functions in Lepr^Nos1KO mice are only modestly affected by the genetic ablation of LepRb in these neurons. Thus, hypothalamic LepRb^NOS1 neurons are a key site of action of the leptin-mediated control of systemic energy balance.