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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 Article has an altmetric score of 9

Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance

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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 7

TRX2 loss induces excessive mtROS and cytosolic mtDNA release in BAT.

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TRX2 loss induces excessive mtROS and cytosolic mtDNA release in BAT.
(A...
(A and B) mtROS were detected by MitoSOX in iBAT. Data are presented as arbitrary fluorescence unit (AFU). n = 5. (C) mtROS were detected by MitoSOX (red) and mitoPY1 (green) in freshly isolated iBAT. Data are presented as relative fluorescence unit (RFU) by taking WT as 1.0. n = 6. (D) Western blot analysis of redox proteins in BAT. Relative protein levels and PRX3 dimer/monomer ratios are presented as fold changes by taking WT as 1.0. n = 2. (E–H) Mitochondrial structures of iBAT by EM. (E) Representative EM images. White boxes denote magnified areas, and arrowheads indicated mitochondria. Quantification of mitochondrial numbers (F), damaged mitochondria percentage (G), and mitochondria with opening outer membrane (H). Ten fields were randomly chosen for each group (n = 3). (I) mtDNA copy number of iBAT (n = 3). Tert was used as a nuclei DNA control. (J and K) mtROS were detected by MitoTracker (green) and MitoSOX (red) in primary brown adipocytes. Arrows indicate MitoSOX+ cells. Quantification of RFU is shown in K (n = 3). (L and M) Cytosolic DNA detected by costaining for TOM20 (red) and double-stranded DNA (green) in primary brown adipocytes. Boxes denote magnified areas, and arrows indicate DNA released to the cytoplasm that is quantified in M. (N and O) Cytosolic mtDNA in freshly purified mature brown adipocytes from WT and Trx2BATKO mice was detected by PCR. (N) Tert expression. (O) Cytosolic mtDNA contents were determined by qPCR with 3 sets of specific primers. Relative mtDNA contents are presented as fold changes by taking WT as 1.0 (n = 5). 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 (F–H, N, and O) or 2-tailed Student’s t test (B, C, I, K, and M). Scale bars: 100 μm (A); 0.5 μm (E); 10 μm (J and L). Original magnification for higher magnification images, ×1260 (E and L).

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