Dysfunctional BCAAs catabolism protests from diet-induced obesity via IRF4/BCATm pathway in skeletal muscle
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ABSTRACT:
PROVIDER: PRJNA750721 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15295319.fastq.gz | Fastqsanger.gz | |||
| SRR15295320.fastq.gz | Fastqsanger.gz | |||
| SRR15295321.fastq.gz | Fastqsanger.gz | |||
| SRR15295322.fastq.gz | Fastqsanger.gz | |||
| SRR15295323.fastq.gz | Fastqsanger.gz |
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Project description:It is well established that obese animals and humans show deficiencies in skeletal muscle content and metabolism. However, the mechanisms under how skeletal muscle metabolism affects systemic energy homeostasis is not well-defined. Here, we compared the skeletal muscle transcriptome from obese and lean controls in different species. We found an immune-responsive transcription factor interferon regulatory factor 4 (IRF4) was conserved to be increased in obese subjects from the three species (humans, non-human primates and mice). Thus, we demonstrated that loss of IRF4 specifically in skeletal muscle of mice showed protection against the metabolic effects of high-fat diet, with unexpected increased plasma and muscle branched-chain amino acid (BCAA) levels. Conversely, overexpression of skeletal muscle IRF4 caused obesity and insulin resistance, with decreased BCAA contents. Mechanistically, IRF4 can transcriptionally regulate branched-chain aminotransferase isozyme (BCATm) expression, and that overexpression of BCATm can reverse the effects of IRF4 depletion regarding to metabolic phenotypes. Further, we demonstrated ablation of IRF4 in skeletal muscle increased mitochondrial activity and glycogen synthesis in a BCATm- dependent manner. These studies establish IRF4 as a novel driver of BCAA metabolism via BCATm in skeletal muscle and may interpret the BCAAs paradox in obesity.
2024-07-29 | GSE181107 | GEO
Project description:Skeletal muscle is not only a primary site for glucose uptake and storage, but also a reservoir for amino acids stored as protein. How the metabolism of these two fuels is coordinated in skeletal muscle is incompletely understood. Here, we demonstrate that interferon regulatory factor 4 (IRF4) integrate glucose and amino acids flux by regulating glycogen synthesis and branched-chain-amino acid (BCAA) metabolism in skeletal muscle. Mice with IRF4 specifically knocked out in skeletal muscle (MI4KO) showed elevated plasma BCAAs and skeletal muscle glycogen content, decreased adiposity and body weight, along with increased energy expenditure, remarkable improvements in glucose and insulin tolerance, and protection from diet-induced obesity (DIO). Loss of IRF4 caused downregulation of the mitochondrial branched-chain aminotransferase isozyme (BCATm) in myocytes, which encodes for the enzyme catalyzing the first step of BCAA metabolism. Lack of IRF4 also led to the upregulation of protein targeting to glycogen (PTG), which is associated with enhanced mitochondrial Complex II activity and mitochondria number. Additionally, overexpression of IRF4 in skeletal muscle caused obesity and reduced exercise capacity. Mechanistically, we found that IRF4 directly regulates both BCATm and PTG expression, and that overexpression of BCATm can partially reverse the effects of IRF4 deletion. These studies establish IRF4 as a novel driver of both glucose and BCAA metabolism in skeletal muscle.
2019-08-30 | GSE136623 | GEO
Project description:Metabolic regulation of BCAAs and glycogen via IRF4 in skeletal muscle
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Project description:Previously we found that Irf4-deficient T cells were dysfunctional and unable to reject heart allografts and checkpoint blockade treatment could reinvigorate dysfunctional Irf4-deficient T cells and enable them reject heart allografts. But shortly after the reinvigoration those T cells went back to dysfunctional state. TCR-transgenic TEa CD4+ T cells (B6 background) recognize a Balb/c I-Eα allopeptide presented by B6 antigen presenting cells, and were used to assess the effects of immune checkpoint blockades on Irf4-deficient alloreactive T cells. WT, Irf4-/- and checkpoint blockade treated Irf4-/- TEa CD4+ T cells were isolated from Balb/c heart transplanted B6 mice, followed by microarray analysis. To define un-restored gene expressions in Irf4-deficient alloreactive T cells upon immune checkpoint blockades, we compared genes expression level among three groups. We revealed that checkpoint blockade restored the expression levels of the majority of wild-type T cell-expressed genes in Irf4-/- T cells, indicating the reinvigoration of Irf4-/- T cells. The remaining un-restored genes following checkpoint blockade, though minimal in number, may be responsible for the reinvigorated Irf4-/- T cells to become re-dysfunction.
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Project description:It is well established that obese animals and humans show deficiencies in skeletal muscle content and metabolism. However, the mechanisms under how skeletal muscle metabolism affects systemic energy homeostasis is not well-defined. Here, we compared the skeletal muscle transcriptome from obese and lean controls in different species. We found an immune-responsive transcription factor interferon regulatory factor 4 (IRF4) was conserved to be increased in obese subjects from the three species (humans, non-human primates and mice). Thus, we demonstrated that loss of IRF4 specifically in skeletal muscle of mice showed protection against the metabolic effects of high-fat diet, with unexpected increased plasma and muscle branched-chain amino acid (BCAA) levels. Conversely, overexpression of skeletal muscle IRF4 caused obesity and insulin resistance, with decreased BCAA contents. Mechanistically, IRF4 can transcriptionally regulate branched-chain aminotransferase isozyme (BCATm) expression, and that overexpression of BCATm can reverse the effects of IRF4 depletion regarding to metabolic phenotypes. Further, we demonstrated ablation of IRF4 in skeletal muscle increased mitochondrial activity and glycogen synthesis in a BCATm- dependent manner. These studies establish IRF4 as a novel driver of BCAA metabolism via BCATm in skeletal muscle and may interpret the BCAAs paradox in obesity.
2023-12-12 | GSE180906 | GEO
Project description:In this study Guo et al. revealed an endocrine pathway regulated by skeletal muscle IRF4 that manipulates liver pathology. Mice with skeletal muscle specific ablation of IRF4 show ameliorated liver steatosis, inflammation, and fibrosis, without changes in body weight on nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis of mouse serum suggested that follistatin-like protein 1 (FSTL1) might link the communication between muscle and liver. Dual luciferase assays showed that IRF4 could transcriptionally regulate FSTL1 and reconstitution of FSTL1 expression in muscle of F4MKO mice was sufficient to restore the liver pathology. Furthermore, co-culture experiments verified that FSTL1 exerts its function in hepatocyte, macrophage, and hepatic satellite cells through CD14 and DIP2A, CD14, DIP2A, respectively. In human, serum FSTL1 is increased in NASH patients, but the mRNA level of Fstl1 and its receptors are decreased in NASH liver biopsy, suggesting the increased serum FSTL1 is from skeletal muscle as studied in F4MKO mice. These data unveiled a signaling pathway from skeletal muscle to liver via IRF4-FSTL1-DIP2A/CD14 in the pathogenesis of NASH.
2023-09-13 | PXD045324 | Pride
Project description:To define molecular basis underlying dysfunction of Irf4-deficient T cells. We found that Irf4-deficient T cells were dysfunctional and unable to infiltrate and reject heart allografts, and then investigated the molecular basis underlying dysfunction of Irf4-deficient T cells. Irf4-deficient and wild type B6 CD4+ T cells were activated in vitro for two days, followed by microarray analysis. We found that dysfunction of Irf4-deficient T cells is not only due to impaired effector differentiation, but also involves an altered transcriptional programme that allows the expression of essential negative regulators of T-cell function.
2017-06-01 | GSE83283 | GEO
Project description:Obesity is characterized by accumulation of T cells in insulin-sensitive tissues, including the visceral adipose tissue (VAT), that can interfere with the insulin signaling pathway eventually leading to insulin resistance (IR) and type 2 diabetes. Here, we found that PD-1+CD4 conventional T (Tconv) cells, endowed with a transcriptomic and functional profile of partially dysfunctional cells, are diminished in VAT of obese patients with dysglycemia (OB-Dys). These cells showed enhanced capacity to recirculate into the bloodstream and had a non-restricted TCRβ repertoire divergent from that of normoglycemic obese and lean individuals. PD-1+CD4 Tconv were reduced in the circulation of OB-Dys, exhibited an altered migration potential, and were detected in the liver of patients with non-alcoholic steatohepatitis. The findings suggest that dysglycemia in individuals with obesity is associated with recirculation of a heterogeneous population of partially dysfunctional PD-1+CD4 Tconv cells. These changes may contribute to the inter-organ crosstalk underlying IR
2024-02-09 | GSE237338 | GEO
Project description:Exercise-induced fatigue and exhaustion have been an interesting area for many physiologists.Muscle glycogen is critical forphysical performance. However, how glycogen depletion is manipulated during exercise is not very clear. Our aim here is to assess the impact of interferon regulatory factor 4 (IRF4) on skeletal muscle glycogen and subsequent regulation ofexercise capacity. Skeletal muscle-specific IRF4 knockout mice show normal body weight and insulin sensitivity, but better exercise capacity and increased glycogen content with unaltered triglyceride levels compared to control mice on chow diet. In contrast, mice overexpression of IRF4 display decreased exercise capacity and lower glycogen content. Mechanistically, IRF4 regulates glycogen-associated regulatory subunit protein targeting to glycogen (PTG) to manipulate glucose metabolism. Knockdown of PTG can reverse the effects imposed by the absence of IRF4in vivo. Our studies reveal a regulatory pathway including IRF4/PTG/glycogen synthesis that controlling exercise capacity.
2019-11-19 | GSE140633 | GEO
Project description:Transcriptional profiling of T-cells isolated from spleen of IRF4 -/- mice and cultured under Th17 polarizing conditions for 42 hrs compared to cells similarly isolated and cultured from spleen of IRF4 +/- mice. The aim of the study was to identify global misexpression of genes in IRF4 -/- cells and hence identify key pathways regulated by IRF4 during Th17 differentiation. Two-condition experiment, IRF4 -/- vs IRF4 +/- Th17 cells at 42hrs. Biological replicates: 3 for each condition
2012-09-13 | E-GEOD-40726 | biostudies-arrayexpress