c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice

Wu, Rong; Sun, Jianguang; Wang, Jiqiu; Li, Binhua; Liu, Qingsong; Ning, Guang; Jin, Wanzhu; Yuan, Zengqiang

doi:10.1007/s00125-016-4202-2

Cited by 11 publications

(8 citation statements)

References 50 publications

(72 reference statements)

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“…ITGA5 is expressed in different degrees in mesenchymal stem cells isolated from adipose tissue and white mature adipocytes, which is related to the Hippo pathway, while the Hippo pathway controls tissue growth and regulates cell proliferation, differentiation, and cell death (31)(32)(33). ABL1 is highly expressed in the subcutaneous fat of obese humans and high-fat dietinduced obese mice, and it is able to regulate diet-induced obesity by improving insulin sensitivity in subcutaneous fat (34). HSPG2 is a heparan sulfate proteoglycan, which is a component of the basement membrane and participates in a variety of biological activities.…”

Section: Discussionmentioning

confidence: 99%

Weighted Gene Co-Expression Network Analysis Identifies Key Modules and Central Genes Associated With Bovine Subcutaneous Adipose Tissue

et al. 2022

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BackgroundFat deposition is an important economic trait in livestock and poultry production. However, the relationship between various genes and signal pathways of fat deposition is still unclear to a large extent. The purpose of this study is to analyze the potential molecular targets and related molecular pathways in bovine subcutaneous adipose tissue.ResultsWe downloaded the GSE116775 microarray dataset from Gene Expression Omnibus (GEO). The weighted gene co-expression network (WGCNA) was used to analyze the gene expression profile, and the key gene modules with the highest correlation with subcutaneous adipose tissue were identified, and the functional enrichment of the key modules was analyzed. Then, the “real” Hub gene was screened by in-module analysis and protein–protein interaction network (PPI), and its expression level in tissue samples and adipocytes was verified. The study showed that a total of nine co-expression modules were identified, and the number of genes in these modules ranged from 101 to 1,509. Among them, the blue module is most closely related to subcutaneous adipose tissue, containing 1,387 genes. These genes were significantly enriched in 10 gene ontologies including extracellular matrix organization, biological adhesion, and collagen metabolic process, and were mainly involved in pathways including ECM-receptor interaction, focal adhesion, cAMP signaling pathway, PI3K-AKT signaling pathway, and regulation of lipolysis in adipocytes. In the PPI network and coexpression network, five genes (CAV1, ITGA5, COL5A1, ABL1, and HSPG2) were identified as “real” Hub genes. Analysis of Hub gene expression by dataset revealed that the expression of these Hub genes was significantly higher in subcutaneous adipose tissue than in other tissues. In addition, real-time fluorescence quantitative PCR (qRT-PCR) analysis based on tissue samples and adipocytes also confirmed the above results.ConclusionIn this study, five key genes related to subcutaneous adipose tissue were discovered, which laid a foundation for further study of the molecular regulation mechanism of subcutaneous adipose tissue development and adipose deposition.

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Section: Discussionmentioning

confidence: 99%

Weighted Gene Co-Expression Network Analysis Identifies Key Modules and Central Genes Associated With Bovine Subcutaneous Adipose Tissue

et al. 2022

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“…Immunoblotting was performed as previously described (Wu, Sun, et al, 2017). Briefly, tissues or cells were lysed in lysis buffer,and protein concentration was determined by BCA Protein Assay Kit (Beyotime, China).…”

Section: Methodsmentioning

confidence: 99%

Sodium rutin extends lifespan and health span in mice including positive impacts on liver health

Pan

et al. 2021

British J Pharmacology

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Background and Purpose Ageing is associated with progressive metabolic dysregulation. Rutin is a metabolic regulator with a poor solubility. Using soluble sodium rutin we investigating the effect and mechanisms of rutin in ageing process. Experimental Approach Wild type male mice were treated with or without sodium rutin ( 0.2 mg·ml−1 in drinking water from 8‐month‐old until end of life. Kaplan–Meier survival curve was used for lifespan assay, ageing‐related histopathology analysis and metabolic analysis were performed to determine the effects of chronic sodium rutin on the longevity. Serological test, liver tissue metabolomics and transcriptomics were used for liver function assay. SiRNA knockdown Angptl8 and autophagy flux assay in HepG2 cell lines explored the mechanism through which sodium rutin might impact the function of hepatocyte. Key Results Sodium rutin treatment extends the lifespan of mice by 10%. Sodium rutin supplementation alleviates ageing‐related pathological changes and promotes behaviour performance in ageing mice. Sodium rutin supplementation altered the whole‐body metabolism in mice, which exhibited increased energy expenditure and lower respiratory quotient. Transcriptomics analysis showed that Sodium rutin affected the expression of metabolic genes. Metabolomics analysis showed that Sodium rutin reduced liver steatosis through increased lipid β‐oxidation. Sodium rutin treatment increased the autophagy level both in vivo and in vitro. The inhibition of autophagy partially abolished the sodium rutin‐mediated effect on lipolysis in HepG2 cells. Conclusion and Implications Sodium rutin treatment extends the lifespan and health span of mice with beneficial effects on metabolism, which were achieved by enhancing the autophagy activity in hepatocytes. LINKED ARTICLES This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc

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“…Some EGFR targeting drugs also potently inhibit the tyrosine kinase ABL1, and loss of adipose ABL1 reduces obesity-induced IR in the mouse ( Wu et al, 2017 ). Erlotinib (IR-DR score = +72), which also inhibits ABL1, reduces kidney inflammation and preserves pancreas function and insulin sensitivity in a mouse model of diabetes ( Li et al, 2018b ).…”

Section: Resultsmentioning

confidence: 99%

A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease

Timmons

Anighoro²,

Brogan

et al. 2022

eLife

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Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.

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c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice

Abstract: Our findings define a new biological role for c-Abl in the regulation of diet-induced obesity through improving insulin sensitivity of subcutaneous fat. This suggests it may become a novel therapeutic target in the treatment of metabolic disorders.

Cited by 11 publications

References 50 publications

Weighted Gene Co-Expression Network Analysis Identifies Key Modules and Central Genes Associated With Bovine Subcutaneous Adipose Tissue

Weighted Gene Co-Expression Network Analysis Identifies Key Modules and Central Genes Associated With Bovine Subcutaneous Adipose Tissue

Sodium rutin extends lifespan and health span in mice including positive impacts on liver health

A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease

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