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 6

Glycolytic enzymes are key ISG15 substrates in beige adipocytes.

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Glycolytic enzymes are key ISG15 substrates in beige adipocytes. (A) Gen...
(A) Gene Ontology analysis (biological process) of ISGylated proteins (n = 3). (B) Volcano plot of proteomic analysis. Red dots represent glycolytic enzymes. Black lines indicate significantly enriched or de-enriched proteins (FDR = 0.05) (n = 3). (C) Heatmap of glycolytic protein levels from mass spectrometric analysis (n = 3). (D) Western blot of glycolytic enzymes in beige adipocytes expressing GFP or FLAG-ISG15 pulled down by IgG or anti-FLAG antibody. (E) Extracellular acidification rate (ECAR) of WT and Isg15–/– beige adipocytes (n = 8). 2-DG, 2-dexoy-d-glucose. (F) ECAR in Isg15–/– beige adipocytes expressing GFP or mouse ISG15 (n = 8). mpH, milli pH units. (G) Basal ECAR in WT and Irf3–/– beige adipocytes expressing GFP or mouse ISG15 (n = 8). (H) Basal ECAR in WT and FI3OE beige adipocytes expressing GFP or mouse ISG15 (n = 8). Statistical comparisons were made using 2-way ANOVA (E and F) or 2-tailed Student’s t test (G and H). Data are presented as mean ± SEM. *P < 0.05; #P < 0.05 vs. WT.