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

Vasundhara Kain; Bandish Kapadia; Navin Viswakarma; Sriram Seshadri; Bhumika Prajapati; Prasant K. Jena; Chandana Lakshmi Teja Meda; Maitreyi Subramanian; Sashidhara Kaimal Suraj; Sireesh T. Kumar; Phanithi Prakash Babu; Bayar Thimmapaya; Janardan K. Reddy; Kishore V.L. Parsa; Parimal Misra

doi:10.1038/srep15197

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

Vasundhara Kain, Bandish Kapadia, Navin Viswakarma, Sriram Seshadri, Bhumika Prajapati, Prasant K. Jena, Chandana Lakshmi Teja Meda, Maitreyi Subramanian, Sashidhara Kaimal Suraj, Sireesh T. Kumar, Phanithi Prakash Babu, Bayar Thimmapaya, Janardan K. Reddy, Kishore V.L. Parsa^*, Parimal Misra

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	15197
Journal	Scientific reports
Volume	5
DOIs	https://doi.org/10.1038/srep15197
State	Published - Oct 15 2015

Funding

The authors thank Dr. Brian N. Finck, Washington University, St. Louis for providing GLUT4 promoter constructs. VK, MS, BK and CLTM acknowledge financial support from DBT (RA; BT/PR13527/ BRB/10/765/2010), DBT (RA Fellowship) CSIR (JRF/SRF fellowship) and SERB (SR/FT/LS-131/2009), respectively. The authors are thankful to the funding agencies for providing financial support: PM and KVLP (DBT; BT/PR13527/BRB/10/765/2010); KVLP (SERB; SR/FT/LS-131/2009); PPB (DST, SB/EMEQ-257/2013, Dt.12.7.2013) and JKR (NIH grant R01 DK097249 and R01 DK083163). PM and KVLP are thankful to Dr. Amitabha Chattopadhyay for help with confocal microscopy. PM and KVLP are grateful for the constant encouragement and support from Drs. Venkateswarlu, Javed Iqbal and Uday Saxena. PM and KVLP dedicate this work to the memory of Dr. K. Anji Reddy.

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Kain, V., Kapadia, B., Viswakarma, N., Seshadri, S., Prajapati, B., Jena, P. K., Teja Meda, C. L., Subramanian, M., Kaimal Suraj, S., Kumar, S. T., Prakash Babu, P., Thimmapaya, B., Reddy, J. K., Parsa, K. V. L., & Misra, P. (2015). Co-activator binding protein PIMT mediates TNF-α induced insulin resistance in skeletal muscle via the transcriptional down-regulation of MEF2A and GLUT4. Scientific reports, 5, Article 15197. https://doi.org/10.1038/srep15197

@article{58b9ad1d4b184cfba78a76323ec08a3e,

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.",

author = "Vasundhara Kain and Bandish Kapadia and Navin Viswakarma and Sriram Seshadri and Bhumika Prajapati and Jena, {Prasant K.} and {Teja Meda}, {Chandana Lakshmi} and Maitreyi Subramanian and {Kaimal Suraj}, Sashidhara and Kumar, {Sireesh T.} and {Prakash Babu}, Phanithi and Bayar Thimmapaya and Reddy, {Janardan K.} and Parsa, {Kishore V.L.} and Parimal Misra",

note = "Funding Information: The authors thank Dr. Brian N. Finck, Washington University, St. Louis for providing GLUT4 promoter constructs. VK, MS, BK and CLTM acknowledge financial support from DBT (RA; BT/PR13527/ BRB/10/765/2010), DBT (RA Fellowship) CSIR (JRF/SRF fellowship) and SERB (SR/FT/LS-131/2009), respectively. The authors are thankful to the funding agencies for providing financial support: PM and KVLP (DBT; BT/PR13527/BRB/10/765/2010); KVLP (SERB; SR/FT/LS-131/2009); PPB (DST, SB/EMEQ-257/2013, Dt.12.7.2013) and JKR (NIH grant R01 DK097249 and R01 DK083163). PM and KVLP are thankful to Dr. Amitabha Chattopadhyay for help with confocal microscopy. PM and KVLP are grateful for the constant encouragement and support from Drs. Venkateswarlu, Javed Iqbal and Uday Saxena. PM and KVLP dedicate this work to the memory of Dr. K. Anji Reddy.",

year = "2015",

month = oct,

day = "15",

doi = "10.1038/srep15197",

language = "English (US)",

volume = "5",

journal = "Scientific reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

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, KVL & Misra, P 2015, 'Co-activator binding protein PIMT mediates TNF-α induced insulin resistance in skeletal muscle via the transcriptional down-regulation of MEF2A and GLUT4', Scientific reports, vol. 5, 15197. https://doi.org/10.1038/srep15197

TY - JOUR

T1 - Co-activator binding protein PIMT mediates TNF-α induced insulin resistance in skeletal muscle via the transcriptional down-regulation of MEF2A and GLUT4

AU - Kain, Vasundhara

AU - Kapadia, Bandish

AU - Viswakarma, Navin

AU - Seshadri, Sriram

AU - Prajapati, Bhumika

AU - Jena, Prasant K.

AU - Teja Meda, Chandana Lakshmi

AU - Subramanian, Maitreyi

AU - Kaimal Suraj, Sashidhara

AU - Kumar, Sireesh T.

AU - Prakash Babu, Phanithi

AU - Thimmapaya, Bayar

AU - Reddy, Janardan K.

AU - Parsa, Kishore V.L.

AU - Misra, Parimal

N1 - Funding Information: The authors thank Dr. Brian N. Finck, Washington University, St. Louis for providing GLUT4 promoter constructs. VK, MS, BK and CLTM acknowledge financial support from DBT (RA; BT/PR13527/ BRB/10/765/2010), DBT (RA Fellowship) CSIR (JRF/SRF fellowship) and SERB (SR/FT/LS-131/2009), respectively. The authors are thankful to the funding agencies for providing financial support: PM and KVLP (DBT; BT/PR13527/BRB/10/765/2010); KVLP (SERB; SR/FT/LS-131/2009); PPB (DST, SB/EMEQ-257/2013, Dt.12.7.2013) and JKR (NIH grant R01 DK097249 and R01 DK083163). PM and KVLP are thankful to Dr. Amitabha Chattopadhyay for help with confocal microscopy. PM and KVLP are grateful for the constant encouragement and support from Drs. Venkateswarlu, Javed Iqbal and Uday Saxena. PM and KVLP dedicate this work to the memory of Dr. K. Anji Reddy.

PY - 2015/10/15

Y1 - 2015/10/15

N2 - 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.

AB - 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.

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U2 - 10.1038/srep15197

DO - 10.1038/srep15197

M3 - Article

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AN - SCOPUS:84944704030

SN - 2045-2322

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JO - Scientific reports

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M1 - 15197

ER -

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

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