title: Co-activator binding protein PIMT mediates TNF-α 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-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.
authors.affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.
authors.forename: Vasundhara
authors.initials: V
authors.lastname: Kain
authors.affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.
authors.forename: Bandish
authors.initials: B
authors.lastname: Kapadia
authors.affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.
authors.forename: Navin
authors.initials: N
authors.lastname: Viswakarma
authors.affiliation: Institute of Science, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, India.
authors.forename: Sriram
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: Institute of Science, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, India.
authors.forename: Bhumika
authors.initials: B
authors.lastname: Prajapati
authors.affiliation: Institute of Science, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, India.
authors.forename: Prasant K
authors.initials: PK
authors.lastname: Jena
authors.affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.
authors.forename: Chandana Lakshmi
authors.initials: CL
authors.lastname: Teja Meda
authors.affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.
authors.forename: Maitreyi
authors.initials: M
authors.lastname: Subramanian
authors.affiliation: Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India.
authors.forename: Sashidhara
authors.initials: S
authors.lastname: Kaimal Suraj
authors.affiliation: Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India.
authors.forename: Sireesh T
authors.initials: ST
authors.lastname: Kumar
authors.affiliation: Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India.
authors.forename: Phanithi
authors.initials: P
authors.lastname: Prakash Babu
authors.affiliation: Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Bayar
authors.initials: B
authors.lastname: Thimmapaya
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
authors.affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.
authors.forename: Kishore V L
authors.initials: KV
authors.lastname: Parsa
authors.affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.
authors.forename: Parimal
authors.initials: P
authors.lastname: Misra
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D064326:MEF2 Transcription Factors; C578037:MEF2A protein, rat; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases