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 has increased. However, whether heat stress has an enduring impact on metabolic health remains unclear. Here, we report that mice exposed to heat stress were more susceptible to metabolic dysfunction upon subsequent exposure to an obesogenic diet. Upon heat stress, we found that elevated skin-derived kallikrein-related peptidase 14 (KLK14) imprinted hypothalamic LRRC7+ astrocytes. These astrocytes further suppressed neighboring paraventricular nucleus (PVN)OXT neuron activity via alkB homolog 1, histone H2A dioxygenase (ALKBH1)-mediated epigenetic modification of γ-aminobutyric acid (GABA) synthesis, thus driving visceral fat deposition in a sympathetic nervous-system-dependent manner. Heat stress exposure also increased susceptibility to metabolic dysfunction in human subjects, with vitamin A treatment limiting the production of KLK14 and ameliorating metabolic disturbances in humans and mice. Together, our findings reveal a skin-hypothalamus axis linking heat memory and metabolic dysfunction and highlight that global warming is exacerbating metabolic diseases.