An Intra-Hypothalamic Pathway Modulating Body Temperature and Feeding

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 unconventional pathways originating from a subpopulation of genetically defined excitatory, leptin receptor-expressing 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 connections, inhibit brown adipose tissue (BAT) thermogenesis and reduce body temperature; surprisingly, the VMPO LepR →PVH connection additionally exhibits the unique ability to suppress food intake and also promotes tail vasodilation. Our findings suggest that the excitatory VMPO LepR →PVH loop integrates temperature and caloric information to complement the canonical inhibitory arcuate nucleus (ARC)→PVH pathway. We propose that this novel pathway contributes 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.