Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44106, USA.
Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Nat Commun. 2022 May 18;13(1):2748. doi: 10.1038/s41467-022-30470-w.
Toll-like receptors/Interleukin-1 receptor signaling plays an important role in high-fat diet-induced adipose tissue dysfunction contributing to obesity-associated metabolic syndromes. Here, we show an unconventional IL-1R-IRAKM-Slc25a1 signaling axis in adipocytes that reprograms lipogenesis to promote diet-induced obesity. Adipocyte-specific deficiency of IRAKM reduces high-fat diet-induced body weight gain, increases whole body energy expenditure and improves insulin resistance, associated with decreased lipid accumulation and adipocyte cell sizes. IL-1β stimulation induces the translocation of IRAKM Myddosome to mitochondria to promote de novo lipogenesis in adipocytes. Mechanistically, IRAKM interacts with and phosphorylates mitochondrial citrate carrier Slc25a1 to promote IL-1β-induced mitochondrial citrate transport to cytosol and de novo lipogenesis. Moreover, IRAKM-Slc25a1 axis mediates IL-1β induced Pgc1a acetylation to regulate thermogenic gene expression in adipocytes. IRAKM kinase-inactivation also attenuates high-fat diet-induced obesity. Taken together, our study suggests that the IL-1R-IRAKM-Slc25a1 signaling axis tightly links inflammation and adipocyte metabolism, indicating a potential therapeutic target for obesity.
Toll 样受体/白细胞介素 1 受体信号通路在高脂肪饮食诱导的脂肪组织功能障碍中发挥重要作用，导致肥胖相关代谢综合征。在这里，我们在脂肪细胞中显示了一种非传统的 IL-1R-IRAKM-Slc25a1 信号轴，它重新编程脂肪生成以促进饮食诱导的肥胖。脂肪细胞特异性缺失 IRAKM 可减少高脂肪饮食诱导的体重增加，增加全身能量消耗并改善胰岛素抵抗，伴随脂质积累和脂肪细胞大小减少。IL-1β 刺激诱导 IRAKM Myddosome 易位到线粒体以促进脂肪细胞中的从头脂肪生成。在机制上，IRAKM 与线粒体柠檬酸载体 Slc25a1 相互作用并磷酸化 Slc25a1，以促进 IL-1β 诱导的线粒体柠檬酸向细胞质的转运和从头脂肪生成。此外，IRAKM-Slc25a1 轴介导 IL-1β 诱导的 Pgc1a 乙酰化，以调节脂肪细胞中的产热基因表达。IRAKM 激酶失活也可减轻高脂肪饮食诱导的肥胖。综上所述，我们的研究表明，IL-1R-IRAKM-Slc25a1 信号轴紧密连接炎症和脂肪细胞代谢，为肥胖症提供了一个潜在的治疗靶点。
