title: Muscle-Specific Overexpression of PGC-1α Does Not Augment Metabolic Improvements in Response to Exercise and Caloric Restriction.
abstract: This study used mice with muscle-specific overexpression of PGC-1α, a transcriptional coactivator that promotes mitochondrial biogenesis, to determine whether increased oxidative potential facilitates metabolic improvements in response to lifestyle modification. MCK-PGC1α mice and nontransgenic (NT) littermates were fed a high-fat diet (HFD) for 10 weeks, followed by stepwise exposures to voluntary wheel running (HFD+Ex) and then 25% caloric restriction with exercise (Ex/CR), each for an additional 10 weeks with continued HFD. Running and CR improved weight and glucose control similarly in MCK-PGC1α and NT mice. Sedentary MCK-PGC1α mice were more susceptible to diet-induced glucose intolerance, and insulin action measured in isolated skeletal muscles remained lower in the transgenic compared with the NT group, even after Ex/CR. Comprehensive profiling of >200 metabolites and lipid intermediates revealed dramatic group-specific responses to the intervention but did not produce a lead candidate that tracked with changes in glucose tolerance irrespective of genotype. Instead, principal components analysis identified a chemically diverse metabolite cluster that correlated with multiple measures of insulin responsiveness. These findings challenge the notion that increased oxidative capacity defends whole-body energy homeostasis and suggest that the interplay between mitochondrial performance, lipotoxicity, and insulin action is more complex than previously proposed.
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Kari E
authors.initials: KE
authors.lastname: Wong
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Mikus
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Dorothy H
authors.initials: DH
authors.lastname: Slentz
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC Department of Pharmacology and Cancer Biology, Duke University, Durham, NC.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Seiler
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC Department of Pharmacology and Cancer Biology, Duke University, Durham, NC.
authors.forename: Karen L
authors.initials: KL
authors.lastname: DeBalsi
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: Department of Medicine, University of Vermont, Burlington, VT.
authors.forename: Karen I
authors.initials: KI
authors.lastname: Crain
authors.affiliation: Free Radical Biology & Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Kinter
authors.affiliation: Department of Medicine, University of Vermont, Burlington, VT Department of Pediatrics, University of Vermont, Burlington, VT.
authors.forename: C Lawrence
authors.initials: CL
authors.lastname: Kien
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC Department of Pharmacology and Cancer Biology, Duke University, Durham, NC Department of Medicine, Duke University, Durham, NC muoio@duke.edu.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D040901:Proteomics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors