Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance
Yanrui Huang, Jenny H. Zhou, Haifeng Zhang, Alberto Canfran-Duque, Abhishek K. Singh, Rachel J. Perry, Gerald I. Shulman, Carlos Fernandez-Hernando, Wang Min
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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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 4

TRX2 deficiency in BAT impairs thermogenesis.

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TRX2 deficiency in BAT impairs thermogenesis. (A) Intrarectal temperatur...
(A) Intrarectal temperature of 16-week-old WT and Trx2BATKO mice during acute cold intolerance test in the absence of food (n = 6). (B–F) WT and Trx2BATKO mice after 3 days of cold exposure. (B) Intrarectal temperature (n = 6). (C) Food intake during cold exposure. (D) Angptl4 mRNA expression in iBAT (n = 3). (E) Western blots of indicated proteins in iBAT. Relative protein levels are presented as fold changes by taking WT as 1.0. n = 2. (F) Histologic iBAT images. Arrowheads denote large LDs. (G and H) Ex vivo lipolysis assay detecting FFA levels (G) and FFA release efficiency (H) of isolated iBAT treated with saline or ISO (n = 3). (I) In vivo lipolysis assay detecting plasma NEFA (n = 6). (J) PPARα and PPARγ protein expression in iBAT. Relative protein levels are presented by taking saline as 1.0. n = 2 mice. (K) Relative mRNA expression of Ppara (n = 4) and its target genes (n = 3) in iBAT. (L) Ex vivo FA oxidation of iBAT (n = 6). Quantitative data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Two-way ANOVA with Bonferroni’s post hoc tests (A–C), 1-way ANOVA followed by Tukey’s post hoc test (G and I), and 2-tailed Student’s t test (D, H, K, and L). Scale bar: 100 μm (F).