Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis

We show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Lepr inactivation in PNOC neurons increases Npy expression in a subset of hypothalamic PNOC neurons that do not express Agrp and selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOCARC neurons and overexpression of Npy in PNOCARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPYARC neurons as an additional critical mediator of leptin action and a promising target for obesity therapeutics.