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Txnip deficiency causes a susceptibility to acute cold stress with brown fat dysfunction in mice [ChIP-seq]

ABSTRACT: Mammals adaptively regulate energy metabolism in response to environmental changes such as starvation and cold circumstances. Thioredoxin-interacting protein (Txnip), known as a redox regulator, serves as a nutrient sensor regulating energy homeostasis. Txnip is essential for mice to adapt to starvation, but its role in adapting to cold circumstances remains unclear. Here, we identified Txnip as a pivotal factor for maintaining non-shivering thermogenesis in mice. Txnip protein levels in brown adipose tissue (BAT) were upregulated by the acute cold exposure. Txnip-deficient (Txnip-/-) mice acclimated to thermoneutrality (30°C) exhibited significant BAT enlargement and triglyceride accumulation with downregulation of BAT signature and metabolic gene expression. Upon acute cold exposure (5°C), Txnip-/- mice showed a rapid decline in BAT surface temperatures with the failure of increasing metabolic respiration, developing lethal hypothermia. The BAT dysfunction and cold susceptibility in Txnip-/- mice were corrected by acclimation to 16°C, protecting the mice from life-threatening hypothermia. Transcriptomic and metabolomic analysis using dissected BAT revealed that despite preserving glycolysis, the BAT of Txnip-/- mice failed to activate the catabolism of branched-chain amino acids and fatty acids in response to acute cold stress. These findings illustrate that Txnip is required for maintaining basal BAT function and ensuring cold-induced thermogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE251653 | GEO | 2025/01/01

REPOSITORIES: GEO

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Txnip deficiency causes a susceptibility to acute cold stress with brown fat dysfunction in mice [RNA-seq]

Project description:Mammals adaptively regulate energy metabolism in response to environmental changes such as starvation and cold circumstances. Thioredoxin-interacting protein (Txnip), known as a redox regulator, serves as a nutrient sensor regulating energy homeostasis. Txnip is essential for mice to adapt to starvation, but its role in adapting to cold circumstances remains unclear. Here, we identified Txnip as a pivotal factor for maintaining non-shivering thermogenesis in mice. Txnip protein levels in brown adipose tissue (BAT) were upregulated by the acute cold exposure. Txnip-deficient (Txnip-/-) mice acclimated to thermoneutrality (30°C) exhibited significant BAT enlargement and triglyceride accumulation with downregulation of BAT signature and metabolic gene expression. Upon acute cold exposure (5°C), Txnip-/- mice showed a rapid decline in BAT surface temperatures with the failure of increasing metabolic respiration, developing lethal hypothermia. The BAT dysfunction and cold susceptibility in Txnip-/- mice were corrected by acclimation to 16°C, protecting the mice from life-threatening hypothermia. Transcriptomic and metabolomic analysis using dissected BAT revealed that despite preserving glycolysis, the BAT of Txnip-/- mice failed to activate the catabolism of branched-chain amino acids and fatty acids in response to acute cold stress. These findings illustrate that Txnip is required for maintaining basal BAT function and ensuring cold-induced thermogenesis.

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Project description:Brown adipose tissue (BAT) is a thermogenic organ that requires Uncoupling Protein 1 (UCP1) to dissipate chemical energy as heat, to defend core body temperature against hypothermia, and counteract obesity and metabolic diseases1. However, the transcriptional mechanism ensuring BAT thermogenic capacity for survival prior to environmental cold is unknown. Here we show histone deacetylase 3 (HDAC3) is a required transcriptional regulator of BAT enhancers to ensure thermogenic aptitude and survival. Mice with genetic ablation of HDAC3 become severely hypothermic and fail to survive acute cold exposure. UCP1 is nearly absent in BAT lacking HDAC3 and there is marked down-regulation of mitochondrial oxidative phosphorylation (OXPHOS) genes. Remarkably, although HDAC3 canonically functions as a transcriptional corepressor2, HDAC3 functions as a coactivator of the estrogen-related receptor _ (ERR_) in BAT, and loss of HDAC3 leads to robust global down-regulation of ERR±-driven enhancers. HDAC3 coactivation of ERR_ is mediated through deacetylation of PGC-1_ and is required for basal transcription of Ucp1, OXPHOS, and Pgc-1_. Thus, HDAC3 uniquely primes Ucp1 and thermogenic gene transcription to ensure immediate BAT-driven thermogenesis upon acute exposure to dangerously cold temperatures.

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Histone Deacetylase 3 Prepares Brown Adipose Tissue For Acute Thermogenic Challenge [ChIP-Seq, GRO-Seq]

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