美国贝克曼研究所Anying Song研究组近日取得一项新成果。经过不懈努力，他们的最新研究揭示了脂肪细胞异质性的双稳态调节控制着产热。相关论文于2026年11月11日发表于国际顶尖学术期刊《自然》杂志上。

棕色脂肪细胞（BAs）是调节能量稳态的产热细胞，与年龄相关的产热下降会导致冷敏感。研究人员此前鉴定出一个UCP1低表达的BA亚群（以下简称BA-L细胞），它与经典的UCP1高表达BAs（以下简称BA-H细胞）共存。在此，研究人员表明，由中性粒细胞和巨噬细胞分泌的IL-1β将附近的BAs稳定在BA-L状态。具体而言，IL-1β稳定己糖-6-磷酸脱氢酶（H6PD）蛋白免于降解，以确保活性糖皮质激素的产生，后者激活糖皮质激素受体（GR，由Nr3c1编码）并增加其靶基因G蛋白信号调节因子2（Rgs2）的表达，从而抑制UCP1表达。冷暴露降低IL-1β水平，这一过程依赖交感神经支配，导致H6PD降解和BA-L细胞向BA-H细胞转化，从而增强UCP1依赖性产热。环境温度升高则触发相反的事件。在冷暴露期间对BA特异性诱导性敲除Nr3c1会使这些细胞锁定在BA-H状态，导致小鼠回到室温数天后仍持续产热并增加能量消耗。值得注意的是，衰老棕色脂肪组织中IL-1β升高，导致BA-H/BA-L比率锁定在低水平并出现冷不耐受。在老年小鼠中抑制GR可恢复BA-H/BA-L比率，恢复产热并增加能量消耗。研究人员的发现揭示了BA异质性的时空神经-免疫调控，该调控决定产热，并为老年人冷敏感性增加的机制提供了基础性理解。

附：英文原文

Title: Bistable regulation of adipocyte heterogeneity governs thermogenesis

Author: Song, Anying, Wang, Yifan, Wang, Guan, Bae, Marie, Wang, Zhichao, Gao, Guoming, Wu, Zhuyin, Lu, Geming, Meng, Jieyi, Yu, Jiayu, Park, Soojin, Garcia-Ocaa, Adolfo, Fueger, Patrick T., Rao, Loredana, Frontini, Andrea, Liu, Yong, Jiang, Lei, Zhu, Yi, Wang, Qiong A.

Issue&Volume: 2026-11-11

Abstract: Brown adipocytes (BAs) are thermogenic cells that regulate energy homeostasis, and age-related declines in thermogenesis contribute to cold sensitivity1,2,3,4,5. 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.

DOI: 10.1038/s41586-026-11308-7

Source: https://www.nature.com/articles/s41586-026-11308-7