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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, regulate 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 sought whether BAT inflammation regulates systematic metabolism and thermogenesis. By using mice with BAT deficiency of thioredoxin-2 (TRX2), a protein that scavenges mitochondrial reactive oxygen species (ROS), we evaluated the impact of BAT inflammation on metabolism and thermogenesis and its underlying mechanism. Our results describe 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE191009 | GEO | 2022/05/04

REPOSITORIES: GEO

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Lrpprc deficiency in brown adipocytes diminishes cold-induced thermogenesis but improves systemic metabolism

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2021-10-07 | PXD008798 | Pride

Proteome imbalance of mitochondrial electron transport chain in brown adipocytes leads to metabolic benefits

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2018-07-12 | PXD008599 | Pride

Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

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Fam172a deletion in brown adipose tissue protects against HFD-induced obesity by activating the BDH1-BHB pathway

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2023-08-29 | GSE241732 | GEO

The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue

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2021-07-19 | GSE178366 | GEO

Integrated proteome and phosphoproteome analysis of interscapular brown adipose and subcutaneous white adipose tissues upon high fat diet feeding in mouse

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2022-04-01 | PXD032888 | iProX

A map of the PGC-1α- and NT-PGC-1α-regulated transcriptional network in brown adipose tissue [SAGE]

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2018-05-22 | GSE110055 | GEO

A map of the PGC-1α- and NT-PGC-1α-regulated transcriptional network in brown adipose tissue [ChIP-Seq]

2018-05-22 | GSE110053 | GEO

Bulk RNA Sequencing of sorted LepR+ Sympathetic Associated Perineurial Cells

Project description:Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor (LepR)-expressing barrier cells which ensheath sympathetic axon bundles in adipose tissues. These LepR-expressing Sympathetic Perineurial Cells (SPCs) produce IL33, a factor for maintenance and recruitment of regulatory T cell (Treg) and eosinophils in AT. Brown adipose tissues (BAT) of mice lacking IL33 in SPCs (SPCIL33cKO) have fewer Treg and eosinophils, resulting in increased BAT inflammation. These SPCIL33cKO mice are more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCIL33cKO mice have impaired adaptive thermogenesis, and are unresponsive to leptin-induced rescue of metabolic adaptation. We, therefore, identify LepR-expressing SPCs as a source of IL33 which orchestrate an anti-inflammatory environment in BAT, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+ IL33+SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.

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