Andras Franko1, Jürgen-Christoph von Kleist-Retzow2, Susanne Neschen3, Moya Wu3, Philipp Schommers4, Marlen Böse4, Alexander Kunze5, Ursula Hartmann5, Carmen Sanchez-Lasheras6, Oliver Stoehr7, Michael Huntgeburth8, Susanne Brodesser9, Martin Irmler10, Johannes Beckers11, Martin Hrabé de Angelis11, Mats Paulsson12, Markus Schubert13, Rudolf J Wiesner14. 1. 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. 2. 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. 3. Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. 4. Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, 50931 Köln, Germany. 5. Department of Biochemistry, University of Köln, 50931 Köln, Germany. 6. Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Köln, 50674 Köln, Germany. 7. Center for Endocrinology, Diabetes and Preventive Medicine, University of Köln, 50937 Köln, Germany. 8. Department of Internal Medicine III, University of Köln, 50937 Köln, Germany. 9. 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. 10. Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany. 11. 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. 12. 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. 13. 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. 14. 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.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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 hypoinsulinemicSTZmice 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.
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