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

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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/677113v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1ac072forg.highwire.dtl.DTLVardef@10bc88corg.highwire.dtl.DTLVardef@9b9b5corg.highwire.dtl.DTLVardef@1f4e276_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe HPA axis orchestrates cold adaptation. C_LIO_LIACTH activates brown fat thermogenesis in vitro and in vivo via activating MC2R. C_LIO_LIGlucocorticoids drive cold-induced hyperphagia. C_LIO_LIGlucocorticoids have a permissive effect on ACTH function in brown adipocytes. C_LI