IRF3 reduces adipose thermogenesis via ISG15-mediated reprogramming of glycolysis
Shuai Yan, … , Rasheed Ahmad, Evan D. Rosen
Shuai Yan, … , Rasheed Ahmad, Evan D. Rosen
Published February 11, 2021
Citation Information: J Clin Invest. 2021;131(7):e144888. https://doi.org/10.1172/JCI144888.
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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 10

Herc6 is required for adipocyte IRF3-mediated suppression of thermogenesis.

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Herc6 is required for adipocyte IRF3-mediated suppression of thermogene...
(A) Schematic illustrating the strategy for the generation of FI3OE/Cas9 mice. (B) mRNA levels of Herc6 in primary adipocytes and SVF from iWAT of Adipoq-Cre/Cas9 mice injected with AAV-GFP or AAV-Herc6 guide RNA (gRNA) (n = 4). (C) Thermogenic gene expression in iWAT of Cas9 and FI3OE/Cas9 mice injected with AAV-GFP or AAV-Herc6 gRNA followed by 7 days of cold challenge (n = 6). (D) Western blot of UCP1 in iWAT of mice as described in C (n = 4). Statistical comparisons were made using 2-way ANOVA (C and D) or 2-tailed Student’s t test (B). Data are presented as mean ± SEM. *P < 0.05 vs. WT; #P < 0.05 vs. AAV-GFP.