Thermal-state-dependent control of body temperature and feeding by two intra-hypothalamic pathways

The intricate interplay between energy metabolism and body temperature regulation underscores the necessity of finely tuned mechanisms to maintain thermo-energetic homeostasis. Hot environments are known to suppress food intake and to reduce energy expenditure. However, the interplay between thermoregulatory and caloric-regulatory hypothalamic areas remains largely unexplored. In this study, we unveil two pathways originating from a subpopulation of genetically defined leptin receptor-expressing ventromedial preoptic area (POA) neurons (VMPO^LepR) that connect to the paraventricular nucleus of the hypothalamus (PVH) and the dorsomedial hypothalamic nucleus (DMH). Both VMPO^LepR→PVH and VMPO^LepR→DMH pathways modulate brown adipose tissue (BAT) thermogenesis and body temperature, with their impact on body temperature regulation being particularly enhanced in a hot environment. Additionally, the pathways differentially regulate food intake and tail vasodilation, with feeding suppression being more prominent under cooler conditions and thermoregulatory effects more pronounced at elevated ambient temperatures. Our findings suggest that the VMPO^LepR→PVH and VMPO^LepR→DMH pathways integrate temperature and caloric information to complement the canonical inhibitory arcuate nucleus (ARC)→PVH pathway. We propose that these novel pathways contribute to energy and temperature homeostasis in hot environments, offering new insights into previously unrecognized neuronal circuits orchestrating thermo-metabolic balance in response to environmental challenges.