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.
View: Text | PDF
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

×

Figure 12

MCC950 treatment reverses the metabolic benefits of Trx2BATKO mice under nutrient overload.

Options: View larger image (or click on image) Download as PowerPoint
MCC950 treatment reverses the metabolic benefits of Trx2BATKO mice under...
(A) Representative histologic images of iBAT, ingWAT, and liver tissues from 16-week-old HFD-fed WT and Trx2BATKO mice. Arrowheads denote LDs in BAT and liver, whereas arrows denote ingWAT with multilocular LDs. (B) BAT adipocytes with unilocular LD diameter of 20 μm or more and proportion of WAT with multilocular LDs are quantified. n = 6. (C) TG contents of liver from HFD-fed mice with or without MCC950 (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 (B and C). Scale bar: 100 μm (A). (D) A schematic diagram summarizing our findings. TRX2 deficiency in BAT protects from insulin resistance and impairs thermogenesis through the mtDNA/NLRP3 inflammasome pathways. TRX2 ablation in brown adipocytes triggers ROS production and mtDNA release, which induce NLRP3-mediated aberrant innate inflammation in BAT. Consequently, enhanced lipid uptake, with suppressed mitochondrial FA oxidation in BAT, results in the “whitening” of BAT, protecting mice from insulin resistance, but impairing thermogenesis (see text for details).