Regulation of Redox Homeostasis by ATF4-MTHFD2 Axis during White Adipose Tissue Browning
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ABSTRACT:
PROVIDER: PRJNA1249416 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33081121_1.fastq.gz | Fastqsanger.gz | |||
| SRR33081121_2.fastq.gz | Fastqsanger.gz | |||
| SRR33081122_1.fastq.gz | Fastqsanger.gz | |||
| SRR33081122_2.fastq.gz | Fastqsanger.gz | |||
| SRR33081123_1.fastq.gz | Fastqsanger.gz |
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Project description:Maintaining redox balance is crucial for mitochondrial homeostasis. During browning of white adipocytes, both the quality and quantity of mitochondria undergo dramatic changes. However, the mechanisms controlling the redox balance in the mitochondria during this process remain unclear. In this study, we demonstrate that thermogenic activation occurs before mitochondrial biogenesis during cold-induced browning of inguinal white adipose tissue (iWAT) and is accompanied by increased mitochondrial stress and integrated stress response (ISR) signaling. Specifically, cold exposure enhances the expression of ATF4, an ISR effector. Adipocyte-specific deletion of ATF4 results in increased energy expenditure, but paradoxically leads to a lower core body temperature, and heightened pro-inflammation in iWAT after cold exposure, which is restored by the antioxidant, MitoQ. Mechanistically, ATF4 regulates the redox balance through MTHFD2, an enzyme involved in mitochondrial redox homeostasis by NADPH generation. Cold exposure upregulates MTHFD2 expression in an ATF4-dependent manner, and its inhibition by DS18561882 in vivo leads to impaired cold- induced mitochondrial respiration similar to the effects of ATF4 loss. These findings suggest that ATF4 is essential for redox balance via MTHFD2, thereby affecting tissue homeostasis during iWAT browning.
2025-05-13 | GSE294416 | GEO
Project description:In mammals, adaptation to cold environments involves browning of inguinal white adipose tissue (iWAT) to enhance adaptive thermogenesis and maintain body temperature. Immune cells that reside in the adipose tissue are involved in iWAT browning. However, the mechanism by which thermogenesis regulates immune cell composition remains elusive. Here, we revealed that cold-induced activating transcription factor 4 (ATF4) is necessary for maintaining the immune cell composition and supporting iWAT browning. ATF4 and integrated stress response-related genes were highly expressed in iWAT following acute cold exposure. Mice lacking ATF4 exhibited less cold-induced iWAT browning and lower CL316,243-induced oxygen consumption. Mechanistically, the depletion of ATF4 leads to the accumulation of mitochondrial oxidative stress due to the reduction of MTHFD2, a mitochondrial one-carbon metabolism enzyme that contributes to the maintenance of the mitochondrial redox balance. This leads to higher levels of pro-inflammatory cytokines and shifts in adipose tissue macrophage polarization. Together, our findings highlight the critical role of ATF4 in maintaining oxidative stress and adipose tissue inflammatory signaling, thus supporting iWAT browning.
2025-02-15 | GSE255840 | GEO
Project description:ATF4 mediates cold-induced adipose tissue browning by regulating MTHFD2 expression
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Project description:Differentiation of brown adipocytes is a crucial process for adaptive thermogenesis, which is stimulated by various factors. We found robust browning of inguinal white adipose tissue in UCP1/ApoE-DKO mice, but not in ApoE-KO mice, under high-fat diet condition. We used microarray to determine the genes specifically regulated in the browning white adipose tissue in UCP1/ApoE-DKO mice.
2018-10-01 | GSE95273 | GEO
Project description:The adipose tissue is a key site regulating energy metabolism. One of the contributing factors behind this is browning of white adipose tissue (WAT), however, knowledge of the intracellular determinants of browning process remains incomplete. By generating adipocyte-specific Senp2 knockout (Senp2-aKO) mice, here we showed that SENP2 negatively regulates browning by de-conjugating SUMO from C/EBPβ. Senp2-aKO mice were resistant to diet-induced obesity and insulin resistance due to increased energy expenditure and heat production. Senp2 knockout promoted beige adipocyte accumulation in inguinal WAT by upregulation of thermogenic gene expression. In addition, SENP2 knockdown promoted thermogenic adipocyte differentiation of precursor cells isolated from inguinal and epididymal WATs. Mechanistically, sumoylated C/EBPβ, a target of SENP2, suppressed expression of HOXC10, a browning inhibitor, by recruiting a transcriptional repressor DAXX. These findings indicate that a SENP2-C/EBPβ-HOXC10 axis operates for the control of beige adipogenesis in inguinal WAT.
2023-11-27 | GSE189387 | GEO
Project description:The adipose tissue is a key site regulating energy metabolism. One of the contributing factors behind this is browning of white adipose tissue (WAT), however, knowledge of the intracellular determinants of browning process remains incomplete. By generating adipocyte-specific Senp2 knockout (Senp2-aKO) mice, here we showed that SENP2 negatively regulates browning by de-conjugating SUMO from C/EBPβ. Senp2-aKO mice were resistant to diet-induced obesity and insulin resistance due to increased energy expenditure and heat production. Senp2 knockout promoted beige adipocyte accumulation in inguinal WAT by upregulation of thermogenic gene expression. In addition, SENP2 knockdown promoted thermogenic adipocyte differentiation of precursor cells isolated from inguinal and epididymal WATs. Mechanistically, sumoylated C/EBPβ, a target of SENP2, suppressed expression of HOXC10, a browning inhibitor, by recruiting a transcriptional repressor DAXX. These findings indicate that a SENP2-C/EBPβ-HOXC10 axis operates for the control of beige adipogenesis in inguinal WAT.
2023-11-27 | GSE189326 | GEO
Project description:PurposeMethylenetetrahydrofolate dehydrogenase 2 (MTHFD2) has been reported to be overexpressed in non-small-cell lung cancer (NSCLC) and to correlate with malignant proliferation. However, the mechanism of high MTHFD2 expression in NSCLC has not been clarified.MethodsqPCR, western blot, and immunofluorescence experiments were used to measure the expression of related mRNAs and proteins. Cell apoptosis was measured by flow cytometry and TUNEL assays. The CCK-8 assay was used to determine cell viability. Flow cytometry was used to analyze the cell cycle. ROS, H2O2, MDA, SOD, and NADPH/NADP+ were evaluated by relevant assay kits. Transfection of siRNA or vectors was used to downregulate or upregulate gene expression. Dual-luciferase reporter gene assays were used to evaluate the regulated relationship between MTHFD2 and ATF4 or MYC.ResultsMTHFD2 was highly expressed in NSCLC cells. Knockdown of MTHFD2 inhibited proliferation and increased apoptosis. Furthermore, oxidative factors significantly increased, while antioxidant factors significantly decreased in NSCLC cells with MTHFD2 knockdown, indicating that MTHFD2 was involved in NSCLC progression through the redox pathway. Although MTHFD2 was downregulated with ATF4 silencing, the dual-luciferase reporter assay suggested that ATF4 did not directly mediate MTHFD2 transcription. Further studies revealed that MYC had a transcriptional effect on MTHFD2 and was also regulated by ATF4. PCR, and western blotting experiments with ATF4 knockdown and MYC overexpression as well as ATF4 overexpression and MYC knockdown proved that ATF4 stimulated MTHFD2 through MYC mediation.ConclusionsATF4 promoted high expression of MTHFD2 in NSCLC dependent on MYC.
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Project description:As obesity has becoming an urged issue nowadays, delineation of the mechanisms of WAT tissue white-browning and beige adipose origin are of important topic. By the use of snRNA-seq, we can outline LepR cells play important role in the white-browning process and investigate the mechanisms participate at different white-browning treatments.
2022-11-06 | GSE216925 | GEO
Project description:We report mRNA seq during time course of white preadipocyte browning from WT and HMGN1 and HMGN2 double knockout (DKO) mice . Moreover, we support our finding that loss of HMGN promotes white adipocyte browning with RNA seq of WT and DKO MEFs transdifferentiation into brown-like adipocytes.
2022-10-19 | GSE193338 | GEO
Project description:We report single-cell RNA seq (scRNA seq) at day 0 and day 6 of white preadipocyte browning from WT and HMGN1 and HMGN2 double knockout (DKO) mice. This supports our finding that loss of HMGN promotes white adipocyte browning with RNA seq of WT and DKO MEFs transdifferentiation into brown-like adipocytes.
2022-10-19 | GSE193462 | GEO