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 6

TRX2 loss in BAT contributes minimally to whole-body EE.

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TRX2 loss in BAT contributes minimally to whole-body EE. (A–D) Mice were...
(A–D) Mice were fed or fasted for 24 hours from 7 am. (A) Representative histologic images of iBAT from 16-week-old WT and Trx2BATKO mice. Three sections from each mouse (n = 3 mice). (B) Cd36 expression in iBAT (n = 3). (C) Gene expression of FA oxidation–related genes in iBAT (n = 3 mice). (D) Intrarectal temperature (n = 6). (E–I). Mice were subjected to metabolic cage evaluation. Mice were individually placed in metabolic cages (CLAMs) and allowed to acclimatize for 48 hours before readings were taken. Mice were fasted for 24 hours and refed for 48 hours (n = 5 for WT, n = 4 for KO in fasted, n = 3 for KO in refed). EE (E), oxygen consumption (VO2) (F), food intake (G), physical activity counts (H), and RER (I) were measured. Analyses were performed in male mice. Quantitative data are presented as mean ± SEM. *P < 0.05; ***P < 0.001. Significance was assessed by 2-tailed Student’s t test. Scale bar: 100 μm (A).