A skin-hypothalamus axis couples heat stress and metabolic dysfunction

  • Cell. 2026 Jun 11;189(12):3571-3588.e27. doi: 10.1016/j.cell.2026.03.045.
Hai-Yan Zhou  1 ,  Xu Feng  2 ,  Jie Wen  2 ,  Yao Xiao  2 ,  Li-Wen Wang  2 ,  Lin-Yun Chen  2 ,  Gen-Qing Xie  3 ,  Jia-Jun Zhao  4 ,  Yan Huang  5 ,  Xiang-Hang Luo  6
Affiliations
  • 1. Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disease (Xiangya Hospital), Changsha 410008, Hunan, China; FuRong Laboratory, Changsha 410078, Hunan, China.
  • 2. Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China.
  • 3. The First People's Hospital of Xiangtan City, Xiangtan 411100, Hunan, China.
  • 4. Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China. Electronic address: [email protected].
  • 5. Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disease (Xiangya Hospital), Changsha 410008, Hunan, China. Electronic address: [email protected].
  • 6. Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disease (Xiangya Hospital), Changsha 410008, Hunan, China; FuRong Laboratory, Changsha 410078, Hunan, China; The First People's Hospital of Xiangtan City, Xiangtan 411100, Hunan, China. Electronic address: [email protected].
PMID: 42019490 DOI: 10.1016/j.cell.2026.03.045
Abstract

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.

Keywords
LRRC7(+) astrocytes; heat memory; hypothalamus; metabolic dysfunction; skin.
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