@article{e634e516a31e4fab825088fc60c05727,
title = "TFAM enhances fat oxidation and attenuates high-fat diet-induced insulin resistance in skeletal muscle",
abstract = "Diet-induced insulin resistance (IR) adversely affects human health and life span. We show that musclespecific overexpression of human mitochondrial transcription factor A (TFAM) attenuates high-fat diet (HFD)-induced fat gain and IR in mice in conjunction with increased energy expenditure and reduced oxidative stress. These TFAM effects on muscle are shown to be exerted by molecular changes that are beyond its direct effect on mitochondrial DNA replication and transcription. TFAM augmented the muscle tricarboxylic acid cycle and citrate synthase facilitating energy expenditure. TFAM enhanced muscle glucose uptake despite increased fatty acid (FA) oxidation in concert with higher b-oxidation capacity to reduce the accumulation of IR-related carnitines and ceramides. TFAM also increased pAMPK expression, explaining enhanced PGC-1a and PPARb, and reversing HFD-induced GLUT4 and pAKT reductions. TFAM-induced mild uncoupling is shown to protect mitochondrial membrane potential against FA-induced uncontrolled depolarization. These coordinated changes conferred protection to TFAM mice against HFD-induced obesity and IR while reducing oxidative stress with potential translational opportunities.",
author = "Koh, {Jin Ho} and Johnson, {Matthew L.} and Surendra Dasari and LeBrasseur, {Nathan K.} and Ivan Vuckovic and Henderson, {Gregory C.} and Cooper, {Shawna A.} and Shankarappa Manjunatha and Ruegsegger, {Gregory N.} and Shulman, {Gerald I.} and Lanza, {Ian R.} and Nair, {K. Sreekumaran}",
note = "Funding Information: Acknowledgments. The authors thank Katherine Klaus and Dawn Morse (Mayo Clinic) for skillful technical support. Funding. The study was supported by the David Murdock Dole Professorship (K.S.N.) and by grants from the National Institutes of Health Center for Scientific Review (DK-007198 to M.L.J., TRDK-007352 to G.C.H., and RO1-DK-41973 to K.S.N.) and the Mayo Clinic Metabolomics Core (supported by grant U24-DK-100469). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. J.-H.K. conducted all cell line studies and molecular phenotyping studies. J.-H.K., S.D., and I.V. conducted metabolite measurements. J.-H.K., S.D., and K.S.N. drafted the manuscript. J.-H.K., M.L.J., S.D., N.K.L., I.V., G.C.H., S.A.C., G.N.R., G.I.S., and I.R.L. conducted various aspects of the study. M.L.J. performed mitochondrial phenotyping studies. S.D. conducted statistical analyses. N.K.L., G.C.H., and S.A.C. conducted animal studies. G.I.S. performed hyperinsulinemic clamp and muscle glucose uptake measurements at the Yale Core Laboratory. K.S.N. designed and supervised the study and performed the data analysis and interpretation. All authors contributed to the final version of the manuscript. K.S.N. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Data and Resource Availability. The data sets generated during and/ or analyzed during the current study are available from the corresponding author upon reasonable request. No applicable resources were generated or analyzed during the current study. Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association.",
year = "2019",
month = aug,
day = "1",
doi = "10.2337/db19-0088",
language = "English (US)",
volume = "68",
pages = "1552--1564",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "8",
}