Remodeling of purinergic signaling in the paraventricular hypothalamus promotes hyperphagic obesity and insulin resistance

Body energy homeostasis is tightly regulated by hypothalamic neural circuits. However, their remodeling upon metabolic challenges remains incompletely characterized, thus complicating the development of safe medications against the surge of metabolic diseases. Oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVH) are one of the key effectors regulating energy balance. In this work, we report that high-fat diet (HFD) feeding in mice evokes spatiotemporally selective ATP release from astrocytes (Inflares) in the PVH, accompanied by the expression of hematopoietic lineage-specific ADP/ATP receptor P2Y ₁₂ on local OXT (PVH ^OXT ) neurons. Strikingly, increased purinergic signaling leads to impaired responsiveness of PVH ^OXT neurons accompanied by hyperphagic obesity and insulin resistance in mice. Conversely, loss of P2Y ₁₂ in PVH ^OXT neurons attenuates metabolic phenotypes, illustrating that such remodeling is both necessary and sufficient to induce metabolic phenotypes. Inflares were also induced by hyperglycemia, while emergence of P2Y ₁₂ on OXT neurons of patients with diabetes mellitus suggests an evolutionary conserved purinergic response to various metabolic challenges and its potential as a drug target. Accordingly, nasal administration of clinically approved doses of P2Y ₁₂ inhibitors counteracts obesity in mice and non-human primates, paving the way for application of these compounds in patients with metabolic disorders.