A skin-hypothalamus axis couples heat stress and metabolic dysfunction

With the ongoing rise in global temperatures, heat stress is increasingly implicated in chronic metabolic disorders; however, whether a transient high-temperature experience leads to enduring metabolic vulnerability and persistent hypothalamic adaptations remains unclear. To address this question, we established a controlled heat stress (HS) mouse model. Eight-week-old male mice with comparable body weights were assigned to HS or paired-fed (PF) conditions. HS mice were exposed to 37 °C for 6 h during the dark phase for 1 week with ad libitum access to food. PF mice were maintained at room temperature and pair-fed to match the food intake consumed by HS mice during the 6-h exposure window, followed by ad libitum feeding for the remaining 18 h to ensure comparable total daily intake. After HS, mice were returned to room temperature for a 2-week quiescent stage (QS), during which blood glucose and serum corticosterone normalized, indicating recovery from acute stress. Hypothalamic cells were collected from PF, HS, and QS groups for single-cell RNA sequencing to characterize heat stress–associated changes in hypothalamic cellular composition and transcriptional states. We observed a sustained increase in astrocyte abundance after HS that persisted into QS, and identified an expanded astrocyte subpopulation marked by high Lrrc7 expression, providing a foundation for further investigation of persistent hypothalamic responses to heat exposure in the context of metabolic regulation.