Liver adapts mitochondrial function to insulin resistant and diabetic states in mice

Andras Franko, Jürgen Christoph Von Kleist-Retzow, Susanne Neschen, Moya Wu, Philipp Schommers, Marlen Böse, Alexander Kunze, Ursula Hartmann, Carmen Sanchez-Lasheras, Oliver Stoehr, Michael Huntgeburth, Susanne Brodesser, Martin Irmler, Johannes Beckers, Martin Hrabé De Angelis, Mats Paulsson, Markus Schubert, Rudolf J. Wiesner

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50 Scopus citations


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.

Original languageEnglish
Pages (from-to)816-823
Number of pages8
JournalJournal of Hepatology
Issue number4
StatePublished - Apr 2014


  • Insulin receptor
  • Liver metabolism
  • Mitochondrial biogenesis
  • Mitochondrial gene expression
  • Type 2 diabetes mellitus


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