Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance
Yanrui Huang, … , Carlos Fernandez-Hernando, Wang Min
Yanrui Huang, … , Carlos Fernandez-Hernando, Wang Min
Published February 24, 2022
Citation Information: J Clin Invest. 2022;132(9):e148852. https://doi.org/10.1172/JCI148852.
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Research Article Inflammation Metabolism

Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance

Abstract

Brown adipose tissue (BAT), a crucial heat-generating organ, regulates whole-body energy metabolism by mediating thermogenesis. BAT inflammation is implicated in the pathogenesis of mitochondrial dysfunction and impaired thermogenesis. However, the link between BAT inflammation and systematic metabolism remains unclear. Herein, we use mice with BAT deficiency of thioredoxin-2 (TRX2), a protein that scavenges mitochondrial reactive oxygen species (ROS), to evaluate the impact of BAT inflammation on metabolism and thermogenesis and its underlying mechanism. Our results show that BAT-specific TRX2 ablation improves systematic metabolic performance via enhancing lipid uptake, which protects mice from diet-induced obesity, hypertriglyceridemia, and insulin resistance. TRX2 deficiency impairs adaptive thermogenesis by suppressing fatty acid oxidation. Mechanistically, loss of TRX2 induces excessive mitochondrial ROS, mitochondrial integrity disruption, and cytosolic release of mitochondrial DNA, which in turn activate aberrant innate immune responses in BAT, including the cGAS/STING and the NLRP3 inflammasome pathways. We identify NLRP3 as a key converging point, as its inhibition reverses both the thermogenesis defect and the metabolic benefits seen under nutrient overload in BAT-specific Trx2-deficient mice. In conclusion, we identify TRX2 as a critical hub integrating oxidative stress, inflammation, and lipid metabolism in BAT, uncovering an adaptive mechanism underlying the link between BAT inflammation and systematic metabolism.

Authors

Yanrui Huang, Jenny H. Zhou, Haifeng Zhang, Alberto Canfran-Duque, Abhishek K. Singh, Rachel J. Perry, Gerald I. Shulman, Carlos Fernandez-Hernando, Wang Min

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Figure 8

TRX2 deficiency triggers cGAS/STING pathway and NLRP3 inflammasome activation in BAT.

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TRX2 deficiency triggers cGAS/STING pathway and NLRP3 inflammasome activ...
(A) Proinflammatory cytokine mRNA expression in iBAT from 16-week-old WT and Trx2BATKO mice (n = 3). (B) NLRP3 inflammasome-related gene expression of iBAT (n = 4). (C) IL-1β levels of iBAT as detected by ELISA (n = 3). (D) Western blots of cGAS/cGAMP/STING pathway proteins in iBAT. Relative protein levels are presented as fold changes by taking WT as 1.0. n = 2. (E and F) Immunostaining of NF-κB p65 (green) in primary brown adipocytes with DAPI counterstaining. Boxes denote magnified areas, and arrowheads denote nuclear p65 or IRF3. Nuclear p65 translocation (% p65+ nuclei) was quantified. (G and H) Immunostaining of IRF3 (green) in primary brown adipocytes with DAPI counterstaining. Nuclear IRF3 translocation (% IRF3+ nuclei) was quantified. (I) Western blots of inflammasome-related proteins in isolated mature brown adipocytes from iBAT. Relative protein levels are presented as fold changes by taking WT as 1.0. n = 2. (J and K) Inflammasome activation in primary brown adipocytes detected by ASC (red) and NLRP3 (green) colocalization. White arrows indicate ASC+ specks. (K) Quantification of the percentages of cells with ASC specks in 15 randomly selected fields for each sample. Quantitative data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Significance was assessed by 1-way ANOVA followed by Tukey’s post hoc test (A, C, G, H, and I). Scale bar: 10 μm (E, G, and J). Original magnification for higher magnification images, ×1260 (E and G).