Alterations of hepatic energy metabolism in murine models of obesity, diabetes and fatty liver diseasesResearch in context
Bedair Dewidar,
Lucia Mastrototaro,
Cornelia Englisch,
Claudia Ress,
Cesare Granata,
Elisabeth Rohbeck,
Dominik Pesta,
Geronimo Heilmann,
Martin Wolkersdorfer,
Irene Esposito,
Michelle Reina Do Fundo,
Fariba Zivehe,
Aslihan Yavas,
Michael Roden
Affiliations
Bedair Dewidar
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
Lucia Mastrototaro
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
Cornelia Englisch
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
Claudia Ress
Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Christian Doppler Laboratory for Insulin Resistance, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
Cesare Granata
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
Elisabeth Rohbeck
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
Dominik Pesta
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
Geronimo Heilmann
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
Martin Wolkersdorfer
Landesapotheke Salzburg, Department of Production, Hospital Pharmacy, Salzburg, Austria
Irene Esposito
Institute of Pathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Michelle Reina Do Fundo
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
Fariba Zivehe
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
Aslihan Yavas
Institute of Pathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Michael Roden
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Corresponding author. Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany.
Summary: Background: Disturbed hepatic energy metabolism contributes to non-alcoholic fatty liver (NAFLD), but the development of changes over time and obesity- or diabetes-related mechanisms remained unclear. Methods: Two-day old male C57BL/6j mice received streptozotocin (STZ) or placebo (PLC) and then high-fat (HFD) or regular chow diet (RCD) from week 4 (W4) to either W8 or W16, yielding control [CTRL = PLC + RCD], diabetes [DIAB = STZ + RCD], obesity [OBES = PLC + HFD] and diabetes-related non-alcoholic steatohepatitis [NASH = STZ + HFD] models. Mitochondrial respiration was measured by high-resolution respirometry and insulin-sensitive glucose metabolism by hyperinsulinemic-euglycemic clamps with stable isotope dilution. Findings: NASH showed higher steatosis and NAFLD activity already at W8 and liver fibrosis at W16 (all p < 0.01 vs CTRL). Ballooning was increased in DIAB and NASH at W16 (p < 0.01 vs CTRL). At W16, insulin sensitivity was 47%, 58% and 75% lower in DIAB, NASH and OBES (p < 0.001 vs CTRL). Hepatic uncoupled fatty acid oxidation (FAO)-associated respiration was reduced in OBES at W8, but doubled in DIAB and NASH at W16 (p < 0.01 vs CTRL) and correlated with biomarkers of unfolded protein response (UPR), oxidative stress and hepatic expression of certain enzymes (acetyl-CoA carboxylase 2, Acc2; carnitine palmitoyltransferase I, Cpt1a). Tricarboxylic acid cycle (TCA)-driven respiration was lower in OBES at W8 and doubled in DIAB at W16 (p < 0.0001 vs CTRL), which positively correlated with expression of genes related to lipolysis. Interpretation: Hepatic mitochondria adapt to various metabolic challenges with increasing FAO-driven respiration, which is linked to dysfunctional UPR, systemic oxidative stress, insulin resistance and altered lipid metabolism. In a diabetes model, higher TCA-linked respiration reflected mitochondrial adaptation to greater hepatic lipid turnover. Funding: Funding bodies that contributed to this study were listed in the acknowledgements section.