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Overexpression of TFAM Protects 3T3-L1 Adipocytes from NYGGF4 (PID1) Overexpression-Induced Insulin Resistance and Mitochondrial Dysfunction

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Abstract

NYGGF4, also known as phosphotyrosine interaction domain containing 1(PID1), is a recently discovered gene which is involved in obesity-related insulin resistance (IR) and mitochondrial dysfunction. We aimed to further elucidate the effects and mechanisms underlying NYGGF4-induced IR by investigating the effect of overexpressing mitochondrial transcription factor A (TFAM), which is essential for mitochondrial DNA transcription and replication, on NYGGF4-induced IR and mitochondrial abnormalities in 3T3-L1 adipocytes. Overexpression of TFAM increased the mitochondrial copy number and ATP content in both control 3T3-L1 adipocytes and NYGGF4-overexpressing adipocytes. Reactive oxygen species (ROS) production was enhanced in NYGGF4-overexpressing adipocytes and reduced in TFAM-overexpressing adipocytes; co-overexpression of TFAM significantly attenuated ROS production in NYGGF4-overexpressing adipocytes. However, overexpression of TFAM did not affect the mitochondrial transmembrane potential (ΔΨm) in control 3T3-L1 adipocytes or NYGGF4-overexpressing adipocytes. In addition, co-overexpression of TFAM-enhanced insulin-stimulated glucose uptake by increasing Glucose transporter type 4 (GLUT4) translocation to the PM in NYGGF4-overexpressing adipocytes. Overexpression of NYGGF4 significantly inhibited tyrosine phosphorylation of Insulin receptor substrate 1 (IRS-1) and serine phosphorylation of Akt, whereas overexpression of TFAM strongly induced phosphorylation of IRS-1 and Akt in NYGGF4-overexpressing adipocytes. This study demonstrates that NYGGF4 plays a role in IR by impairing mitochondrial function, and that overexpression of TFAM can restore mitochondrial function to normal levels in NYGGF4-overexpressing adipocytes via activation of the IRS-1/PI3K/Akt signaling pathway.

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Acknowledgments

This work was supported by grants from the National Key Basic Research Program of China (2013CB530604) and the National Natural Science Foundation of China (Grant nos. 30973231 and 81270928), the Priority Academic Program Development of Jiangsu Higher Education Institutions (Grant no. 201104013), and the Talent Foundation of Jiangsu Province (Grant no. Hygiene-39). 2012 Graduate Student Innovation Project of Jiangsu province (Grant no. CXLX12_0559).

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Authors and Affiliations

  1. State Key Laboratory of Reproductive Medicine, Department of Pediatrics, Nanjing Maternity and Child Health Hospital Affiliated to Nanjing Medical University, Nanjing, 210029, China

    Chun-Mei Shi, Guang-Feng Xu, Lei Yang, Zi-Yi Fu, Ling Chen, Ya-Hui Shen, Chen-Bo Ji & Xi-Rong Guo

  2. Institute of Pediatrics of Nanjing Medical University, Nanjing, 210029, China

    Chun-Mei Shi, Lei Yang, Ling Chen, Chen-Bo Ji & Xi-Rong Guo

  3. The 82th Hospital of the People’s Liberation Army, Huai’an, 223001, China

    Guang-Feng Xu & Hai-Long Fu

  4. School of Nursing, Nanjing Medical University, Nanjing, China

    Lu Zhu

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  1. Chun-Mei Shi
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Correspondence to Chen-Bo Ji or Xi-Rong Guo.

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Chun-Mei Shi and Guang-Feng Xu contributed equally to this study.

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Shi, CM., Xu, GF., Yang, L. et al. Overexpression of TFAM Protects 3T3-L1 Adipocytes from NYGGF4 (PID1) Overexpression-Induced Insulin Resistance and Mitochondrial Dysfunction. Cell Biochem Biophys 66, 489–497 (2013). https://doi.org/10.1007/s12013-012-9496-1

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