Bistable regulation of adipocyte heterogeneity governs thermogenesis
Year: 2026
Type: article
Abstract: Brown adipocytes (BAs) are thermogenic cells that regulate energy homeostasis, and age-related declines in thermogenesis contribute to cold sensitivity 1–5 . We previously identified a BA subpopulation with low UCP1 expression (hereafter, BA-L cells) that coexists with the classical, high-UCP1-expressing BAs (hereafter, BA-H cells) 6 . Here we show that IL-1β secreted by neutrophils and macrophages stabilizes nearby BAs in the BA-L state. Specifically, IL-1β stabilizes hexose-6-phosphate dehydrogenase (H6PD) protein from degradation to ensure the generation of active glucocorticoids, which activate the glucocorticoid receptor (GR, encoded by Nr3c1 ) and increase the expression of its target gene, regulator of G-protein signalling 2 ( Rgs2 ), thereby suppressing UCP1 expression. Cold exposure reduces IL-1β levels, depending on sympathetic innervation, leading to H6PD degradation and the conversion of BA-L cells to BA-H cells, thereby enhancing UCP1-dependent thermogenesis. Rising environmental temperatures trigger the opposite events. BA-specific inducible deletion of Nr3c1 during cold exposure locks these cells in the BA-H state, leading to persistent thermogenesis and increased energy expenditure days after the mice return to room temperature. Notably, IL-1β is elevated in aged brown adipose tissue, resulting in a locked low BA-H/BA-L ratio and cold intolerance. Suppressing GR in aged mice restores the BA-H/BA-L ratio, resumes thermogenesis and increases energy expenditure. Our findings reveal a spatiotemporal neuronal–immune regulation of BA heterogeneity that governs thermogenesis and offers a fundamental understanding of the mechanisms underlying increased cold sensitivity in older individuals.
Source: Nature
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7225769541