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 1

BAT-specific TRX2 deficiency protects mice from diet-induced hepatic steatosis and hypertriglyceridemia.

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BAT-specific TRX2 deficiency protects mice from diet-induced hepatic ste...
(A) Growth trend of Trx2BATKO and WT mice under NCD (n = 6) or HFD (n = 10). (B) Ratio of adipose depots to body weight from 16-week-old Trx2BATKO (n = 3) and WT (n = 4) mice under HFD. (C) Representative histologic images of iBAT from HFD-fed mice. Arrowheads denote large unilocular LDs. BAT adipocytes with unilocular LD diameter of 20 μm or more were quantified. (D) Representative histologic images of adipose tissues and liver from Trx2BATKO and WT mice under HFD. Arrows denote multilocular LDs in WAT, while arrowheads denote LDs in the liver. Adipocytes with multilocular LDs (%) are quantified. n = 6. (E–H). Lipid profile, including plasma TG (E), LDL-C (F), TC (G), and HDL-C (H) levels from 16-week-old WT and Trx2BATKO mice under HFD (n = 6). (I) Representative BODIPY staining images of liver from mice under HFD. White box denotes magnified areas. Arrowheads denote LDs in the liver. (J) TG contents of liver from HFD-fed mice (n = 3). (K) Expression of lipid metabolic–related genes in livers from HFD-treated mice (n = 3). Quantitative data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Significance was assessed by 2-way ANOVA with Bonferroni’s post hoc tests (A) and 2-tailed Student’s t test (B–D, J, and K). Scale bars: 100 μm (C and D); 25 μm (I). Original magnification for higher magnification images, ×600 (I).