PREreviews of The Hypothalamic–Pituitary–Adrenal Axis Orchestrates Energy Homeostasis during Cold Exposure

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The Hypothalamic–Pituitary–Adrenal Axis Orchestrates Energy Homeostasis during Cold Exposure

by Mireia Llerins Perez, Xinran Gao, Laura Heimerl, Yuanyuan Wang, Katharina Schnabl, Uwe Firzlaff, Harald Luksch, Martin Klingenspor, Nina Henriette Uhlenhaut, Dehua Wang, and Yongguo Li

Posted: September 21, 2025
Server: bioRxiv
DOI: 10.1101/2025.09.18.677113

Abstract

Cold exposure stimulates the sympathetic nervous system (SNS) to activate brown fat thermogenesis and maintain optimal body temperature, while simultaneously triggering compensatory hyperphagia to restore energy balance. The mechanisms coordinating energy expenditure and intake, however, remain unclear. Here, we reveal that the hypothalamic-pituitary-adrenal (HPA) axis plays a dual role in this process: endogenous adrenocorticotropic hormone (ACTH) directly stimulates the melanocortin-2 receptor (MC2R) in brown adipocytes to promote thermogenesis, whereas glucocorticoids drive cold-induced hyperphagia and act permissively to enhance ACTH-mediated energy expenditure. These findings uncover previously unrecognized functions of the HPA axis and a delicate hormonal interplay that orchestrates energy homeostasis during cold stress. Targeting these pathways may offer novel strategies to mitigate hyperphagic responses associated with increased energy expenditure, with potential implications for obesity treatment.

Highlights

The HPA axis orchestrates cold adaptation.
ACTH activates brown fat thermogenesis in vitro and in vivo via activating MC2R.
Glucocorticoids drive cold-induced hyperphagia.
Glucocorticoids have a permissive effect on ACTH function in brown adipocytes.

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PREreview by Ranea-Robles P. et al. of ASAPbio Metabolism Crowd

Authored by Ranea-Robles P., Ranea-Robles P., Guillermo Sanchez-Delgado, Garcia-Sanchez C, Manuel Fernandez-Escabias, Yolanda Ramirez Casas, Mariana Esparza Palencia, and 4 other authors of ASAPbio Metabolism Crowd

Summary:

This study uncovers a previously unrecognized role of the hypothalamic-pituitary-adrenal (HPA) axis in orchestrating energy homeostasis during cold exposure. The authors demonstrate that exposure to cold activates the HPA axis, leading to the release of adrenocorticotropic hormone (ACTH)…

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