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

Autor:	Kain V; Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India., Kapadia B; Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India., Viswakarma N; Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India., Seshadri S; Institute of Science, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, India., Prajapati B; Institute of Science, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, India., Jena PK; Institute of Science, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, India., Teja Meda CL; Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India., Subramanian M; Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India., Kaimal Suraj S; Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India., Kumar ST; Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India., Prakash Babu P; Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India., Thimmapaya B; Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America., Reddy JK; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America., Parsa KV; Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India., Misra P; Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2015 Oct 15; Vol. 5, pp. 15197. Date of Electronic Publication: 2015 Oct 15.
DOI:	10.1038/srep15197
Abstrakt:	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.
Databáze:	MEDLINE
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