A skin-hypothalamus axis couples heat stress and metabolic dysfunction
With the ongoing rise in global temperatures, the prevalence of heat stress-related chronic health disorders increases. However, whether heat stress has an enduring outcome on metabolic health remains unclear. Here, we report that mice with heat stress experience were more susceptible to metabolic dysfunction, especially visceral fat accumulation, upon subsequent exposure to an obesogenic diet. We found that skin-derived KLK14, elevated upon heat stress, imprinted a unique group of hypothalamic LRRC7+ astrocytes. These cells, accumulating heat memory via epigenetic adaptations, suppress neighboring PVNOXT neuron activities via ALKBH1-mediated epigenetic modification of GABA synthesis, thus driving visceral fat deposition in a sympathetic nervous system-dependent manner. Notably, individuals with heat stress experience were susceptible to suffer from metabolic dysfunction, while vitamin A treatment limited the production of KLK14 and ameliorated their metabolic disturbances. Together, our findings reveal a skin-hypothalamus axis linked heat memory and metabolic dysfunction, and highlights global warming exacerbating metabolic diseases.