A skin-hypothalamus axis couples heat stress and metabolic dysfunction.

Summary

In mice, prior heat exposure increased susceptibility to later diet-induced metabolic dysfunction. Mechanistically, heat stress elevated skin-derived KLK14 that imprinted hypothalamic signaling (involving LRRC7), revealing a peripheral–central axis that links environmental heat to durable metabolic vulnerability.

Key Findings

• Prior heat stress increased susceptibility to diet-induced metabolic dysfunction in mice.
• Heat stress elevated skin-derived KLK14, which imprinted hypothalamic signaling involving LRRC7.
• Defines a skin–hypothalamus axis linking environmental heat to durable metabolic vulnerability.

Clinical Implications

While preclinical, these findings suggest that cumulative heat exposure may be a modifiable risk factor for metabolic disease and nominate the KLK14–hypothalamic axis as a potential therapeutic target. Public health strategies mitigating heat exposure could have downstream metabolic benefits.

Limitations

• Preclinical mouse study; human generalizability remains to be established.
• Intervention reversibility, duration of imprinting, and precise cellular targets require further delineation.

Future Directions

Validate the KLK14–hypothalamus axis in humans, quantify heat exposure–metabolic risk relationships epidemiologically, and test pharmacologic or behavioral interventions that modulate this pathway.