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

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          Abstract

          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 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 β-oxidation capacity to reduce the accumulation of IR-related carnitines and ceramides. TFAM also increased pAMPK expression, explaining enhanced PGC1α 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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          Author and article information

          Journal
          Diabetes
          Diabetes
          American Diabetes Association
          0012-1797
          1939-327X
          May 14 2019
          : db190088
          Article
          10.2337/db19-0088
          6692815
          31088855
          508bd947-d06e-4724-8027-2d0552a81e8d
          © 2019

          Free to read

          http://www.diabetesjournals.org/site/license

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