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Diabetes. 2019 May 14. pii: db190088. doi: 10.2337/db19-0088. [Epub ahead of print]

TFAM Enhances Fat Oxidation and Attenuates High Fat Diet Induced Insulin Resistance in Skeletal Muscle.

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Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
Department of Physical Medicine & Rehabilitation, Mayo Clinic, Rochester, MN.
Mayo Clinic Regional Comprehensive Metabolomics Core, Mayo Clinic, Rochester, MN.
Department of Medicine and Cellular and Molecular Physiology, Yale University, New Haven, CT.
Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN


Diet induced insulin resistance (IR) adversely affects human health and life span. We show that muscle specific 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 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 β-oxidation capacity to reduce accumulation IR-related carnitines and ceramides. TFAM also increased pAMPK expression explaining enhanced PGC-1α, and PPARβ 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.


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