title: Liver adapts mitochondrial function to insulin resistant and diabetic states in mice.
abstract: OBJECTIVE
  To determine if diabetic and insulin-resistant states cause mitochondrial dysfunction in liver or if there is long term adaptation of mitochondrial function to these states, mice were (i) fed with a high-fat diet to induce obesity and T2D (HFD), (ii) had a genetic defect in insulin signaling causing whole body insulin resistance, but not full blown T2D (IR/IRS-1(+/-) mice), or (iii) were analyzed after treatment with streptozocin (STZ) to induce a T1D-like state.
  
  
  METHODS
  Hepatic lipid levels were measured by thin layer chromatography. Mitochondrial respiratory chain (RC) levels and function were determined by Western blot, spectrophotometric, oxygen consumption and proton motive force analysis. Gene expression was analyzed by real-time PCR and microarray.
  
  
  RESULTS
  HFD caused insulin resistance and hepatic lipid accumulation, but RC was largely unchanged. Livers from insulin resistant IR/IRS-1(+/-) mice had normal lipid contents and a normal RC, but mitochondria were less well coupled. Livers from severely hyperglycemic and hypoinsulinemic STZ mice had massively depleted lipid levels, but RC abundance was unchanged. However, liver mitochondria isolated from these animals showed increased abundance and activity of the RC, which was better coupled.
  
  
  CONCLUSIONS
  Insulin resistance, induced either by obesity or genetic manipulation and steatosis do not cause mitochondrial dysfunction in mouse liver. Also, mitochondrial dysfunction is not a prerequisite for liver steatosis. However, severe insulin deficiency and high blood glucose levels lead to an enhanced performance and better coupling of the RC. This may represent an adaptation to fuel overload and the high energy-requirement of an unsuppressed gluconeogenesis.
authors.affiliation: Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, 50931 Köln, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Andras
authors.initials: A
authors.lastname: Franko
authors.affiliation: Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, 50931 Köln, Germany; Department of Pediatrics, University of Köln, 50924 Köln, Germany; Center for Molecular Medicine Cologne, CMMC, University of Köln, 50931 Köln, Germany.
authors.forename: Jürgen-Christoph
authors.initials: JC
authors.lastname: von Kleist-Retzow
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Neschen
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Moya
authors.initials: M
authors.lastname: Wu
authors.affiliation: Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, 50931 Köln, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Schommers
authors.affiliation: Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, 50931 Köln, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Böse
authors.affiliation: Department of Biochemistry, University of Köln, 50931 Köln, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kunze
authors.affiliation: Department of Biochemistry, University of Köln, 50931 Köln, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Hartmann
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Köln, 50674 Köln, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanchez-Lasheras
authors.affiliation: Center for Endocrinology, Diabetes and Preventive Medicine, University of Köln, 50937 Köln, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stoehr
authors.affiliation: Department of Internal Medicine III, University of Köln, 50937 Köln, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Huntgeburth
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Köln, 50935 Köln, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50674 Köln, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Technische Universität München, WZW - Center of Life and Food Science Weihenstephan, Chair of Experimental Genetics, 85350 Freising-Weihenstephan, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Technische Universität München, WZW - Center of Life and Food Science Weihenstephan, Chair of Experimental Genetics, 85350 Freising-Weihenstephan, Germany.
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Center for Molecular Medicine Cologne, CMMC, University of Köln, 50931 Köln, Germany; Department of Biochemistry, University of Köln, 50931 Köln, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50674 Köln, Germany.
authors.forename: Mats
authors.initials: M
authors.lastname: Paulsson
authors.affiliation: Center for Molecular Medicine Cologne, CMMC, University of Köln, 50931 Köln, Germany; Center for Endocrinology, Diabetes and Preventive Medicine, University of Köln, 50937 Köln, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50674 Köln, Germany. Electronic address: markus.schubert@uk-koeln.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Schubert
authors.affiliation: Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, 50931 Köln, Germany; Center for Molecular Medicine Cologne, CMMC, University of Köln, 50931 Köln, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50674 Köln, Germany. Electronic address: rudolf.wiesner@uni-koeln.de.
authors.forename: Rudolf J
authors.initials: RJ
authors.lastname: Wiesner
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000503:physiopathology*; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology; D015870:Gene Expression; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D007473:Ion Channels / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000502:physiology*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000503:physiopathology; D010085:Oxidative Phosphorylation; D018892:Proton-Motive Force; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071246:Uncoupling Protein 2
chemical_list: D055504:Insulin Receptor Substrate Proteins; D007473:Ion Channels; C526295:Irs1 protein, mouse; D024101:Mitochondrial Proteins; D000071246:Uncoupling Protein 2; D000226:Mitochondrial ADP, ATP Translocases; D011972:Receptor, Insulin
keywords: Insulin receptor; Liver metabolism; Mitochondrial biogenesis; Mitochondrial gene expression; Type 2 diabetes mellitus