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A skin-hypothalamus axis couples heat stress and metabolic dysfunction
Hai-Yan Zhou1, Xu Feng2, Jie Wen2
1Department 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.
Cell
|April 22, 2026
Summary
Global warming increases heat stress, worsening metabolic dysfunction. Heat exposure imprints skin-derived kallikrein-related peptidase 14 (KLK14) in the hypothalamus, impairing neurons and increasing visceral fat. Vitamin A may help.
Area of Science:
- Endocrinology
- Neuroscience
- Environmental Health
Background:
- Rising global temperatures are linked to increased chronic health disorders.
- The enduring impact of heat stress on metabolic health is not well understood.
Purpose of the Study:
- To investigate the enduring effects of heat stress on metabolic health.
- To elucidate the molecular mechanisms linking heat stress, the skin-hypothalamus axis, and metabolic dysfunction.
Main Methods:
- Mice exposed to heat stress were subsequently fed an obesogenic diet.
- Investigated the role of skin-derived kallikrein-related peptidase 14 (KLK14) and hypothalamic astrocytes.
- Examined the impact of alkB homolog 1 (ALKBH1) on paraventricular nucleus (PVN) neuron activity and GABA synthesis.
- Assessed metabolic dysfunction in human subjects and the effect of vitamin A treatment.
Main Results:
- Heat-stressed mice showed increased susceptibility to diet-induced metabolic dysfunction.
- Elevated KLK14 in skin imprinted hypothalamic LRRC7+ astrocytes, suppressing PVN OXT neuron activity.
- ALKBH1-mediated epigenetic modification of GABA synthesis drove sympathetic nervous system-dependent visceral fat deposition.
- Vitamin A treatment reduced KLK14 production and ameliorated metabolic disturbances in both mice and humans.
Conclusions:
- A novel skin-hypothalamus axis links heat memory to metabolic dysfunction.
- Global warming exacerbates metabolic diseases through this pathway.
- Targeting KLK14, potentially with vitamin A, offers a therapeutic strategy for heat-induced metabolic disturbances.
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