title: Genetic activation of pyruvate dehydrogenase alters oxidative substrate selection to induce skeletal muscle insulin resistance.
abstract: The pyruvate dehydrogenase complex (PDH) has been hypothesized to link lipid exposure to skeletal muscle insulin resistance through a glucose-fatty acid cycle in which increased fatty acid oxidation increases acetyl-CoA concentrations, thereby inactivating PDH and decreasing glucose oxidation. However, whether fatty acids induce insulin resistance by decreasing PDH flux remains unknown. To genetically examine this hypothesis we assessed relative rates of pyruvate dehydrogenase flux/mitochondrial oxidative flux and insulin-stimulated rates of muscle glucose metabolism in awake mice lacking pyruvate dehydrogenase kinase 2 and 4 [double knockout (DKO)], which results in constitutively activated PDH. Surprisingly, increased glucose oxidation in DKO muscle was accompanied by reduced insulin-stimulated muscle glucose uptake. Preferential myocellular glucose utilization in DKO mice decreased fatty acid oxidation, resulting in increased reesterification of acyl-CoAs into diacylglycerol and triacylglycerol, with subsequent activation of PKC-θ and inhibition of insulin signaling in muscle. In contrast, other putative mediators of muscle insulin resistance, including muscle acylcarnitines, ceramides, reactive oxygen species production, and oxidative stress markers, were not increased. These findings demonstrate that modulation of oxidative substrate selection to increase muscle glucose utilization surprisingly results in muscle insulin resistance, offering genetic evidence against the glucose-fatty acid cycle hypothesis of muscle insulin resistance.
authors.affiliation: Departments of Internal Medicine and Cellular & Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Rahimi
authors.affiliation: Departments of Internal Medicine and Cellular & Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: João-Paulo G
authors.initials: JP
authors.lastname: Camporez
authors.affiliation: Departments of Internal Medicine and Cellular & Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Max C
authors.initials: MC
authors.lastname: Petersen
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Dominik
authors.initials: D
authors.lastname: Pesta
authors.affiliation: Departments of Internal Medicine and Cellular & Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Perry
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.affiliation: Departments of Internal Medicine and Cellular & Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510 gerald.shulman@yale.edu.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002952:Citric Acid Cycle; D004041:Dietary Fats / Q000494:pharmacology / Q000633:toxicity; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D007527:Isoenzymes; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C116917:acylcarnitine; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D005947:Glucose; D002331:Carnitine
keywords: diacylglycerol; insulin action; liquid chromatography mass spectrometry; nuclear magnetic resonance; protein kinase C theta