Enhanced purinergic signaling in the paraventricular hypothalamus induces hyperphagic obesity and insulin resistance

Body energy homeostasis is tightly regulated by hypothalamic neural circuits. However, their remodeling upon metabolic stress remains incompletely characterized, translating to unprecedented challenges to develop safe medications against the surge of metabolic diseases. Oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVH) are one of the key appetite-suppressing effectors within the melanocortin system. In this work, we report that metabolic stress in mice evokes spatiotemporally selective ATP release (Inflares) from PVH astrocytes, accompanied with the expression of hematopoietic lineage-specific ADP/ATP receptor P2Y ₁₂ on OXT (PVH ^OXT ) neurons. Importantly, “ectopic” emergence of P2Y ₁₂ on OXT neurons of patients with diabetes mellitus suggests an evolutionary conserved purinergic response to metabolic stress. Strikingly, increased purinergic signaling leads to impaired responsiveness of PVH ^OXT neurons accompanied with hyperphagic obesity and insulin resistance in mice. Moreover, nasal administration of clinically approved doses of P2Y ₁₂ inhibitors counteracts diet-induced obesity and insulin resistance in mice and spontaneous weight gain in monkeys, paving the way for application of these compounds in patients with metabolic disorders.