Oxytocin signaling in the posterior hypothalamus prevents hyperphagic obesity in mice

Decades of studies have revealed molecular and neural circuit bases for body weight homeostasis. Neural hormone oxytocin (OT) has received attention in this context because it is produced by neurons in the paraventricular hypothalamic nucleus (PVH), a known output center of hypothalamic regulation of appetite. OT has an anorexigenic effect, as shown in human studies, and can mediate satiety signals in rodents. However, the function of OT signaling in the physiological regulation of appetite has remained in question, because whole-body knockout (KO) of OT or OT receptor (OTR) has little effect on food intake. We herein show that acute conditional KO (cKO) of OT selectively in the adult PVH, but not in the supraoptic nucleus, markedly increases body weight and food intake, with an elevated level of plasma triglyceride and leptin. Intraperitoneal administration of OT rescues the hyperphagic phenotype of the PVH OT cKO model. Furthermore, we show that cKO of OTR selectively in the posterior hypothalamic regions, which include the primary centers for appetite regulations, phenocopies hyperphagic obesity. Collectively, these data functionally reveal that OT signaling in the posterior hypothalamic regions suppresses excessive food intake.