Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver

Santhosh Satapati, Nishanth E. Sunny, Blanka Kucejova, Xiaorong Fu, Tian Teng He, Andrés Méndez-Lucas, John M. Shelton, Jose C. Perales, Jeffrey D. Browning, Shawn C. Burgess

Research output: Contribution to journalArticlepeer-review

284 Scopus citations


The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo 2H/ 13C tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial β-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis.

Original languageEnglish (US)
Pages (from-to)1080-1092
Number of pages13
JournalJournal of lipid research
Issue number6
StatePublished - Jun 2012


  • Fatty acid/metabolism
  • Inflammation
  • Mitochondria
  • Nonalcoholic fatty liver disease
  • Obesity; gluconeogenesis
  • Oxidative stress
  • Tricarboxylic acid cycle

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology


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