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 11

ISG15 is positively correlated with insulin sensitivity and glucose homeostasis.

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ISG15 is positively correlated with insulin sensitivity and glucose home...
(A) Isg15 mRNA expression correlates with BMI in human subjects. (B) Western blot of free ISG15 and ISG15 conjugates in primary adipocytes from chow- and HFD-fed mice. (C) Body weight of male WT and Isg15–/– mice during high-fat feeding (n = 8–10). (D) Body composition of male WT and Isg15–/– mice after 16 weeks of HFD feeding (n = 8–10). (E) Adipose depot and liver weight of male WT and Isg15–/– mice after 16 weeks of HFD feeding (n = 8–10). (F) H&E staining of adipose tissues of male WT and Isg15–/– mice after 16 weeks of HFD feeding. Scale bar: 200 μm. (G) Hepatic triglyceride content of male WT and Isg15–/– mice after 16 weeks of HFD feeding (n = 8–10). (H) H&E staining of liver of male WT and Isg15–/– mice after 16 weeks of HFD feeding. Scale bar: 200 μm. (I) Insulin tolerance test (ITT) performed in male WT and Isg15–/– mice after 16 weeks of HFD feeding (n = 8–10). Right panel: Area above the curve of ITT (n = 8–10). (J) Glucose tolerance test (GTT) performed in mice as described as D. Right panel: Area under the curve of GTT (n = 8–10). (K) Fed and fasting plasma insulin levels in mice as described as D (n = 8–10). Statistical comparisons were made using 2-way ANOVA (C, I, and J) or 2-tailed Student’s t test (D, E, and K). Data are presented as mean ± SEM. *P < 0.05.