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Co-activator binding protein PIMT mediates TNF-? induced insulin resistance in skeletal muscle via the transcriptional down-regulation of MEF2A and GLUT4.

ABSTRACT: The mechanisms underlying inflammation induced insulin resistance are poorly understood. Here, we report that the expression of PIMT, a transcriptional co-activator binding protein, was up-regulated in the soleus muscle of high sucrose diet (HSD) induced insulin resistant rats and TNF-? exposed cultured myoblasts. Moreover, TNF-? induced phosphorylation of PIMT at the ERK1/2 target site Ser(298). Wild type (WT) PIMT or phospho-mimic Ser298Asp mutant but not phospho-deficient Ser298Ala PIMT mutant abrogated insulin stimulated glucose uptake by L6 myotubes and neonatal rat skeletal myoblasts. Whereas, PIMT knock down relieved TNF-? inhibited insulin signaling. Mechanistic analysis revealed that PIMT differentially regulated the expression of GLUT4, MEF2A, PGC-1? and HDAC5 in cultured cells and skeletal muscle of Wistar rats. Further characterization showed that PIMT was recruited to GLUT4, MEF2A and HDAC5 promoters and overexpression of PIMT abolished the activity of WT but not MEF2A binding defective mutant GLUT4 promoter. Collectively, we conclude that PIMT mediates TNF-? induced insulin resistance at the skeletal muscle via the transcriptional modulation of GLUT4, MEF2A, PGC-1? and HDAC5 genes.

SUBMITTER: Kain V

PROVIDER: S-EPMC4606566 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Co-activator binding protein PIMT mediates TNF-α induced insulin resistance in skeletal muscle via the transcriptional down-regulation of MEF2A and GLUT4.

Kain Vasundhara V Kapadia Bandish B Viswakarma Navin N Seshadri Sriram S Prajapati Bhumika B Jena Prasant K PK Teja Meda Chandana Lakshmi CL Subramanian Maitreyi M Kaimal Suraj Sashidhara S Kumar Sireesh T ST Prakash Babu Phanithi P Thimmapaya Bayar B Reddy Janardan K JK Parsa Kishore V L KV Misra Parimal P

Scientific reports 20151015

The mechanisms underlying inflammation induced insulin resistance are poorly understood. Here, we report that the expression of PIMT, a transcriptional co-activator binding protein, was up-regulated in the soleus muscle of high sucrose diet (HSD) induced insulin resistant rats and TNF-α exposed cultured myoblasts. Moreover, TNF-α induced phosphorylation of PIMT at the ERK1/2 target site Ser(298). Wild type (WT) PIMT or phospho-mimic Ser298Asp mutant but not phospho-deficient Ser298Ala PIMT mutan ...[more]

PMID: 26468734

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Project description:Panax notoginseng saponins (PNS) are a commonly used traditional medicine to treat diabetes in China. Recent studies have confirmed their anti-diabetic effects, but the underlying mechanisms have remained unclear. The present study was designed to explore whether PNS decrease hyperglycemia by improving insulin sensitivity in skeletal muscle and to elucidate the molecular mechanisms. The anti-diabetic effects of PNS were analyzed in a skeletal myoblast cell line, C2C12, and in high fat diet-induced diabetic KKAy mice. C2C12 cells were treated with PNS (50, 100, and 200 μg·L-1 ) and examined for glucose uptake, cell viability and expression of components of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. KKAy mice were intraperitoneally injected with PNS (200 mg·kg-1 ) for 6 weeks. Body weight, blood glucose, serum insulin, serum lipid, glucose and insulin tolerance were measured to evaluate the anti-diabetic effects of PNS. Pathological changes, apoptosis and the PI3K-AKT signaling pathway were analyzed in KKAy skeletal muscle. PNS significantly increased insulin-induced glucose uptake, but did not affect the cell viability of C2C12 cells. In addition, PNS reduced blood glucose and serum insulin levels and improved glucose tolerance and insulin tolerance of KKAy mice. Pathological changes and apoptosis of skeletal muscle were relieved by PNS treatment. Moreover, PNS treatment enhanced expression of mRNA encoding IRS1 and GLUT4, as well as the protein expression of phosphorylated (p) -insulin receptor substrate 1 (IRS1), p-PI3K, p-AKT and glucose transporter type 4 (GLUT4) in C2C12 and KKAy mouse muscle. Collectively, these data indicate that PNS reduces hyperglycemia and insulin resistance through up-regulating GLUT4 expression and the IRS1-PI3K-AKT signaling pathway. Furthermore, PNS alleviated diabetes skeletal muscle pathological damage. Thus, our data suggest that PNS may be promising anti-diabetic compounds.

Dataset Information

Co-activator binding protein PIMT mediates TNF-? induced insulin resistance in skeletal muscle via the transcriptional down-regulation of MEF2A and GLUT4.

Publications

Co-activator binding protein PIMT mediates TNF-α induced insulin resistance in skeletal muscle via the transcriptional down-regulation of MEF2A and GLUT4.

Similar Datasets

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