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

• Published in: Cell biochemistry and biophysics Vol. 66; no. 3; pp. 489 - 497
• Main Authors: Shi, Chun-Mei, Xu, Guang-Feng, Yang, Lei, Fu, Zi-Yi, Chen, Ling, Fu, Hai-Long, Shen, Ya-Hui, Zhu, Lu, Ji, Chen-Bo, Guo, Xi-Rong
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.07.2013; Springer Nature B.V
• Subjects: 3T3-L1 Cells; Adenosine Triphosphate - metabolism; Adipocytes - drug effects; Adipocytes - metabolism; Adipocytes - pathology; Animals; Biochemistry; Biological and Medical Physics; Biomedical and Life Sciences; Biophysics; Biotechnology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Biology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression; Glucose - metabolism; Glucose Transporter Type 4 - metabolism; Insulin - metabolism; Insulin - pharmacology; Insulin Resistance; Life Sciences; Membrane Potential, Mitochondrial - drug effects; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mitochondrial Size - drug effects; Original Paper; Pharmacology/Toxicology; Phosphorylation - drug effects; Protein Transport - drug effects; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Transcription Factors - genetics; Transcription Factors - metabolism; Translocation; NYGGF4; Obesity; Insulin resistance; TFAM; Mitochondrial function
• ISSN: 1085-9195; 1559-0283
• DOI: 10.1007/s12013-012-9496-1

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.