Diabetologie und Stoffwechsel 2012; 7 - LB_2
DOI: 10.1055/s-0032-1314766

Transient increase in mitochondrial oxidative capacity during the development of insulin resistance in a mouse model of non-alcoholic fatty liver

T Jelenik 1, G Séquaris 1, J Szendrödi 1, 2, J Kotzka 3, E Phielix 1, B Knebel 4, P Nowotny 1, HJ Partke 1, D Müller-Wieland 5, M Roden 1, 2
  • 1Deutsches Diabetes-Zentrum, Leibniz-Institut für Diabetesforschung an der Heinrich-Heine-Universität, Düsseldorf, Germany
  • 2Universitätsklinik Düsseldorf, Heinrich-Heine Universität, Düsseldorf, Germany
  • 3Institut für Klinische Diabetologie, Deutsches Diabetes Zentrum, Leibniz Zentrum für Diabetes Forschung an der Heinrich-Heine-Universität, Düsseldorf, Germany
  • 4Institut für Klinische Biochemie und Pathobiochemie, Deutsches Diabetes Zentrum, Leibniz Zentrum für Diabetes Forschung an der Heinrich-Heine-Universität, Düsseldorf, Germany
  • 5Asklepios Klinik St. Georg, Hamburg, Germany

Non-alcoholic fatty liver (NAFL) and ectopic lipid storage in skeletal muscle have been associated with insulin resistance and abnormal mitochondrial function in obesity and type 2 diabetes. The underlying causal relationships are yet unclear. The aim of this study was to determine the role of mitochondrial function during the development of lipid-induced NAFL and insulin resistance.

We examined liver and muscle metabolism in 18- and 36-weeks-old female mice with secondary NAFL due to adipose tissue-specific overexpression of the sterol regulatory-element binding protein-1c (aP2-SREBP-1c: AP2; n=6–7) and in age- and sex-matched wild-type controls on C57BL/6 background (CON; n=6–7). Insulin sensitivity was determined in 36-weeks-old mice by hyperinsulinemic-euglycemic clamps in combination with the isotope glucose technique. Mitochondrial oxidative capacity was measured in permeabilized tissues using high-resolution respirometry (Oroboros Instruments) and mitochondrial content was assessed from the ratio of mitochondrial DNA to nuclear DNA, using quantitative PCR.

Mean liver weight was 37% and 86% higher (p<0.001) in 18-weeks-old and in 36-weeks-old AP2 mice when compared to CON. Mitochondrial oxidative capacity was improved in 18-weeks-old AP2 mice as assessed by 75% greater pyruvate-dependent mitochondrial respiration in liver (p<0.05) and 93% greater fatty acid-dependent mitochondrial respiration in muscle (p<0.05). On the other hand, 36-weeks-old AP2 mice displayed 25% lower (p<0.05) pyruvate-dependent muscle mitochondrial respiration. Mitochondrial content in muscle and liver remained unchanged. Basal endogenous glucose production (EGP) was doubled in AP2 mice at the age of 36-weeks (31±4, CON: 17±2mg/kg/min; p<0.05). These results were in accordance with higher 6-h fasting serum glucose (216±16, CON: 108±14mg/dl; p<0.05). Furthermore, 36-weeks-old AP2 mice had 43% lower insulin-mediated glucose disposal in peripheral tissues (33±4, CON: 57±9mg/kg/min; p<0.05). Insulin suppression of EGP as well as serum non-esterified fatty acids was not affected by the AP2 genotype.

Initially, hepatic steatosis transiently increases oxidative capacity to compensate for elevated energy supply. However, later stages of NAFL are associated with decreased oxidative capacity and impaired insulin sensitivity in muscle of AP2 mice.

Acknowledgements: German Diabetes Association Menarini, Dr. Skröder Foundation