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 1

Adipocyte-specific IRF3 deficiency increases thermogenic gene expression.

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Adipocyte-specific IRF3 deficiency increases thermogenic gene expression...
(A) Schematic diagram showing generation of FI3KO mice. (B) Irf3 mRNA expression in isolated primary adipocytes from inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) of 8-week-old WT and FI3KO mice (n = 6). (C) Western blot of IRF3 protein in SVF from iWAT and eWAT of 8-week-old WT and FI3KO male mice (n = 3). (D) Thermogenic gene expression in brown adipose tissue (BAT) of chow-fed WT and FI3KO mice after 7 days of cold challenge (n = 8–10). (E) Western blot of UCP1 in iWAT and BAT of mice as described in D (n = 3). (F) UCP1 staining of iWAT of WT and FI3KO mice as described in D. Scale bar: 100 μm. Statistical comparisons were made using 2-tailed Student’s t test (B and D). All data are mean ± SEM. *P < 0.05.