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 9

TRX2 loss–driven NLRP3 inflammasome activation relies on mtDNA release in BAT.

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TRX2 loss–driven NLRP3 inflammasome activation relies on mtDNA release i...
Primary brown adipocytes were differentiated and cultured in the absence or presence of indicated inhibitors or siRNAs for 4 days. (A–C) Effects of CsA on mtDNA release and activation of the cGAS/STING and NLRP3 inflammasome pathways. WT and KO primary brown adipocytes were treated with CsA or vehicle (DMSO). (A) Immunostaining for cytosolic dsDNA (with mitochondrial marker Tom20), nuclear IRF3, or ASC/NLRP3 specks. Boxes denote magnified areas, and arrows denote cytosolic mtDNAs, nuclear IRF3, and ASC+ specks. (B) Nuclear IRF3 translocation (% IRF3+ nuclei) and percentages of ASC speck+ cells were quantified. n = 10 random fields. (C) Western blots for the cGAS/STING and NLRP3 inflammasome pathways. Relative protein levels are presented as fold changes by taking WT as 1.0. (D–F) Effects of MCC950 on mtDNA release and activation of the cGAS/STING and NLRP3 inflammasome pathways. WT and KO primary brown adipocytes were treated with MCC950 or vehicle (DMSO). (D) Western blots for the cGAS/STING and NLRP3 inflammasome pathways. Relative protein levels are presented as fold changes by taking WT as 1.0. (E) Immunostaining of cytosolic dsDNA, IRF3 translocation, and NLRP3-ASC colocalization in primary brown adipocytes treated with MCC950. Boxes denote magnified areas, and arrows denote cytosolic mtDNAs, nuclear IRF3, and ASC+ specks. (F) Nuclear IRF3 translocation (% IRF3+ nuclei) and percentages of ASC speck+ cells were quantified. n = 10 random fields. (G) mRNA expression of lipid metabolism–related genes in WT and KO primary brown adipocytes treated with MCC950 or vehicle. Relative mRNA levels are presented as fold changes by taking WT as 1.0. All experiments were repeated 3 times (n = 3). 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. Scale bars: 10 μm. Original magnification for higher magnification images, ×1260.