Medial preoptic PNOC neurons constrain brown adipose tissue thermogenesis and energy expenditure

The preoptic area (POA) of the hypothalamus is a key neural hub for thermoregulation, yet its role in modulating energy expenditure during caloric excess remains poorly defined. Here, we characterize prepronociceptin (PNOC)-expressing neurons in the medial POA (PNOCmPOA) that inhibit brown adipose tissue (BAT) thermogenesis and systemic energy expenditure. Chemogenetic activation of PNOCmPOA neurons reduced BAT activity, core temperature, energy expenditure, and glucose tolerance through inhibitory projections to the dorsomedial hypothalamus (DMH). In contrast, silencing or ablation of PNOCmPOA neurons increased BAT thermogenesis. Furthermore, PNOCmPOA activation promoted non-REM sleep, coupling thermoregulatory and arousal states. These findings define a hypothalamic circuit that limits postprandial arousal, thermogenesis, and energy dissipation, contributing to the pathophysiology of obesity. Targeting the PNOCmPOA→DMH pathway may provide a new therapeutic strategy to enhance BAT function in metabolic disease.