Alpha4 is Critical for Adipocyte Maintenance and Mitochondrial Homeostasis through Regulation of Insulin Signaling
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ABSTRACT:
PROVIDER: PRJNA865656 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20789873_1.fastq.gz | Fastqsanger.gz | |||
| SRR20789873_2.fastq.gz | Fastqsanger.gz | |||
| SRR20789874_1.fastq.gz | Fastqsanger.gz | |||
| SRR20789874_2.fastq.gz | Fastqsanger.gz | |||
| SRR20789875_1.fastq.gz | Fastqsanger.gz |
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Project description:Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we have investigated the role of phosphatase binding protein Alpha4 (α4) that is essential for the Ser/Thr protein phosphatase PP2A in insulin action/resistance in adipocytes. Unexpectedly, adipocyte-specific inactivation of α4 impairs insulin-induced Akt-mediated Ser/Thr phosphorylation despite a decrease in the PP2A levels. Interestingly, loss of α4 also reduces insulin-induced insulin receptor Tyr phosphorylation. This occurs through decreased association of α4 with Y-box protein 1 (YBX1), resulting in the enhancement of the Tyr phosphatase PTP1B expression. Moreover, adipocyte-specific knockout of α4 results in impaired adipogenesis and altered mitochondrial oxidation leading to increased inflammation, systemic insulin resistance, hepatosteatosis, islet hyperplasia, and impaired thermogenesis. Thus, the α4 /YBX1-mediated pathway of insulin receptor signaling is essential for maintaining insulin sensitivity, normal adipose tissue homeostasis and systemic metabolism.
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Project description:Impaired estrogen production and action are associated with obesity and insulin resistance in male males however the tissues critical for estrogen action in the maintenance of metabolic homeostasis remain inadequately understood. Moreover, the cell specific target genes and molecular actions of estrogen in males remain unknown. We generated male mice with a muscle-specific ERa knockout (MERKO) to determine the role of this hormone nuclear receptor in controlling metabolic function and insulin action in skeletal muscle. Male MERKO mice became insulin resistant with age and accumulated more adipose tissue than floxed control mice. Skeletal muscle was distinguished by enlarged hyper-fused mitochondria that produced increased amounts of superoxide, and this was associated with enhanced proinflammatory signaling. The striking mitochondrial phenotype was accompanied by reduced protein abundance of electron transport chain proteins and the mitochondrial biogenesis marker Pgc1a. Muscle from MERKO mice showed imbalanced protein abundance of mitochondrial fission-fusion proteins most notably marked reductions in total DRP1, MFN1, and OPA1 were observed compared with f/f control. To recapitulate the reduction in DRP1 protein leading to impairment in mitochondrial fission, we generated mice with a muscle-specific heterozygous deletion in Drp1 (mDrp1+/-). mDrp1+/- mice phenocopied the aberrant muscle mitochondrial morphology and dysfunction of the MERKO mice and developed insulin resistance with age. Skeletal muscle ERa is critical for the maintenance of mitochondrial function and metabolic homeostasis in male mice.
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2025-02-03 | PXD046997 | Pride
Project description:Obesity-induced inflammation metabolic dysfunction, but the mechanisms remain elusive. Here we showed that the innate immune factor IRF3 is a direct transcriptional regulator of glucose homeostasis through induction of endogenous FAHFA hydrolase Aig1 in adipocytes. Adipocyte-specific knockout IRF3 protects mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.
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Project description:Background. Alcohol dehydrogenase (ADH1B), encoded by the ADH1B gene, is a cytosolic enzyme mainly known for its role in ethanol catabolism in the liver. A few studies have paved the way to show an equally important role of ADH1B in adipocytes. This study aimed to better identify the cellular mechanisms and signaling pathways involving ADH1B in adipose tissue and to determine if ADH1B variants might contribute to adipose tissue dysfunction. Results. We showed that CRISPR-Cas9-mediated ADH1B knockout (KO) in human adipose stem cells (ASC) abolished adipocyte differentiation and decreased insulin response. This was accompanied by oxidative stress, altered mitochondrial functions, and cellular senescence. Lipidomic analysis revealed that ADH1B deficiency results in a major remodeling of lipid composition in ASC. An ADH1B homozygous loss-of-function variant was also identified in a patient presenting with a lipodystrophic and insulin resistant syndrome associated with major liver dysfunction, leading to early death. Discussion. This translational study underlines the crucial role of ADH1B in adipose tissue. It unveils cellular mechanisms accounting for its key role in adipogenesis, and adipocyte homeostasis. This study also identifies ADH1B as a candidate gene in monogenic forms of lipodystrophic and insulin resistant syndromes.
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