title: Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications.
abstract: Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin-Cre and TFAM floxed alleles. These adiponectin TFAM-knockout (adipo-TFAM-KO) mice had a 75-81% reduction in TFAM in the subcutaneous and intra-abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo-TFAM-KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high-fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications.
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Cecile
authors.initials: C
authors.lastname: Vernochet
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; and.
authors.forename: Federico
authors.initials: F
authors.lastname: Damilano
authors.affiliation: Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mourier
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Olivier
authors.initials: O
authors.lastname: Bezy
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Mori
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Graham
authors.initials: G
authors.lastname: Smyth
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; and.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.affiliation: Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; c.ronald.kahn@joslin.harvard.edu.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000473:pathology; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008060:Lipodystrophy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D052242:Adiponectin; D004268:DNA-Binding Proteins; D045222:Electron Transport Chain Complex Proteins; D006609:High Mobility Group Proteins; C081930:Tfam protein, mouse
keywords: BAT; TFAM; WAT; cardiomegaly; diabetes; hypertension