1. Co-activator binding protein PIMT mediates TNF-α induced insulin resistance in skeletal muscle via the transcriptional down-regulation of MEF2A and GLUT4.
- Author
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Kain V, Kapadia B, Viswakarma N, Seshadri S, Prajapati B, Jena PK, Teja Meda CL, Subramanian M, Kaimal Suraj S, Kumar ST, Prakash Babu P, Thimmapaya B, Reddy JK, Parsa KV, and Misra P
- Subjects
- Animals, Blood Glucose analysis, Cells, Cultured, Down-Regulation drug effects, Glucose Transporter Type 4 genetics, HEK293 Cells, Histone Deacetylases genetics, Histone Deacetylases metabolism, Humans, Insulin Resistance, MEF2 Transcription Factors genetics, MEF2 Transcription Factors metabolism, Male, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Myoblasts, Skeletal cytology, Myoblasts, Skeletal metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phosphorylation drug effects, Protein D-Aspartate-L-Isoaspartate Methyltransferase genetics, Rats, Rats, Wistar, Transcription Factors genetics, Transcription Factors metabolism, Tumor Necrosis Factor-alpha blood, Glucose Transporter Type 4 metabolism, Protein D-Aspartate-L-Isoaspartate Methyltransferase metabolism, Transcription, Genetic drug effects, Tumor Necrosis Factor-alpha pharmacology
- 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-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 mutant abrogated insulin stimulated glucose uptake by L6 myotubes and neonatal rat skeletal myoblasts. Whereas, PIMT knock down relieved TNF-α inhibited insulin signaling. Mechanistic analysis revealed that PIMT differentially regulated the expression of GLUT4, MEF2A, PGC-1α 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-α induced insulin resistance at the skeletal muscle via the transcriptional modulation of GLUT4, MEF2A, PGC-1α and HDAC5 genes.
- Published
- 2015
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