IL-1R-IRAKM-Slc25a1 signaling axis reprograms lipogenesis in adipocytes to promote diet-induced obesity in mice.

Abstract

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.

• Authors: Weiwei Liu, Hao Zhou, Han Wang, Quanri Zhang, Renliang Zhang, Belinda Willard, Caini Liu, Zizhen Kang, Xiao Li, Xiaoxia Li
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 2748 (05 18 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35585086 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Mitochondrial Proteins
• Organic Anion Transporters
• Receptors, Interleukin-1
• Slc25a1 protein, mouse
• Interleukin-1 Receptor-Associated Kinases

Topics

• Adipocytes (metabolism)
• Animals
• Diet, High-Fat
• Insulin Resistance
• Interleukin-1 Receptor-Associated Kinases (metabolism)
• Lipogenesis
• Mice
• Mice, Inbred C57BL
• Mitochondrial Proteins (metabolism)
• Obesity (etiology, metabolism)
• Organic Anion Transporters (metabolism)
• Receptors, Interleukin-1 (metabolism)
• Thermogenesis