IRF3 reduces adipose thermogenesis via ISG15-mediated reprogramming of glycolysis
Shuai Yan, Manju Kumari, Haopeng Xiao, Christopher Jacobs, Shihab Kochumon, Mark Jedrychowski, Edward Chouchani, Rasheed Ahmad, Evan D. Rosen
Shuai Yan, Manju Kumari, Haopeng Xiao, Christopher Jacobs, Shihab Kochumon, Mark Jedrychowski, Edward Chouchani, Rasheed Ahmad, Evan D. Rosen
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Research Article Metabolism

IRF3 reduces adipose thermogenesis via ISG15-mediated reprogramming of glycolysis

Abstract

Adipose thermogenesis is repressed in obesity, reducing the homeostatic capacity to compensate for chronic overnutrition. Inflammation inhibits adipose thermogenesis, but little is known about how this occurs. Here we showed that the innate immune transcription factor IRF3 is a strong repressor of thermogenic gene expression and oxygen consumption in adipocytes. IRF3 achieved this by driving expression of the ubiquitin-like modifier ISG15, which became covalently attached to glycolytic enzymes, thus reducing their function and decreasing lactate production. Lactate repletion was able to restore thermogenic gene expression, even when the IRF3/ISG15 axis was activated. Mice lacking ISG15 phenocopied mice lacking IRF3 in adipocytes, as both had elevated energy expenditure and were resistant to diet-induced obesity. These studies provide a deep mechanistic understanding of how the chronic inflammatory milieu of adipose tissue in obesity prevents thermogenic compensation for overnutrition.

Authors

Shuai Yan, Manju Kumari, Haopeng Xiao, Christopher Jacobs, Shihab Kochumon, Mark Jedrychowski, Edward Chouchani, Rasheed Ahmad, Evan D. Rosen

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Figure 5

Adipocyte IRF3 suppresses UCP1 and mitochondrial activity through ISG15.

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Adipocyte IRF3 suppresses UCP1 and mitochondrial activity through ISG15....
(A) Volcano plot of RNA-Seq data from primary adipocytes isolated from iWAT of 12-week-old chow-fed male WT and FI3OE mice (n = 6). Genes in red are significantly different between WT and FI3OE groups. (B) mRNA levels of Isg15 and Herc6 in primary adipocytes from iWAT, eWAT, and BAT depots in 12-week-old male chow-fed WT and FI3OE mice (n = 6). (C) mRNA levels of Isg15 and Herc6 in primary adipocytes from iWAT, eWAT, and BAT in 12-week-old male chow-fed WT and FI3KO mice (n = 6). (D) Western blot of UCP1 in WT and Isg15–/– beige adipocytes (n = 3). (E) Oxygen consumption rate (OCR) of WT and Isg15–/– beige adipocytes (n = 8). FCCP, carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone;AA, antimycin A. (F) OCR in Isg15–/– beige adipocytes expressing GFP or murine ISG15 (n = 8). (G) Western blot of UCP1 in WT and Irf3–/– beige adipocytes expressing GFP or murine ISG15. (H) Basal OCR in WT and Irf3–/– beige adipocytes expressing GFP or murine ISG15 (n = 8). (I) Western blot of UCP1 and USP18 in WT and FI3OE beige adipocytes expressing GFP or murine USP18. (J) Basal OCR in WT and FI3OE beige adipocytes expressing GFP or murine USP18 (n = 8). Statistical comparisons were made using 2-way ANOVA (E and F) or 2-tailed Student’s t test (B, C, H, and J). Data are presented as mean ± SEM. *P < 0.05; #P < 0.05 vs. GFP.