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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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 4

FI3OE mice display increased diet-induced obesity.

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FI3OE mice display increased diet-induced obesity. (A) Body weight of ma...
(A) Body weight of male WT and FI3OE mice during HFD feeding (n = 8–10). (B) Body composition of male WT and FI3OE mice after 16 weeks of HFD feeding (n = 8–10). (C) Adipose depot and liver weight of male WT and FI3OE mice after 16 weeks of high-fat feeding (n = 8–10). (D and E) Hepatic triglyceride (D) and H&E staining of liver (E) of male WT and FI3OE mice after 16 weeks of HFD feeding (n = 8–10). (F) H&E staining of adipose tissues of male WT and FI3OE mice after 16 weeks of high-fat feeding. Scale bars: 200 μm. (G) Insulin tolerance test (ITT) performed in male WT and FI3OE mice after 6 weeks on HFD. Right panel: Area above the curve of ITT (n = 8–10). (H) Glucose tolerance test (GTT) performed in male WT and FI3OE mice after 6 weeks on HFD. Right panel: Area under the curve of GTT (n = 8–10). Statistical comparisons were made using 2-way ANOVA (A, G, and H) or 2-tailed Student’s t test (B–D). Data are presented as mean ± SEM. *P < 0.05.