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 journalArticle

157 Citations (Scopus)

Abstract

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
Volume53
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Citric Acid Cycle
Pathology
Fatty Liver
Nutrition
Liver
Insulin Resistance
Gluconeogenesis
Insulin
Diet
High Fat Diet
Fats
Mitochondria
Electrons
Oxidation
Biosynthetic Pathways
Electron Transport
Fluxes
Oxidative stress
Fasting
Reactive Oxygen Species

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. / Satapati, Santhosh; Sunny, Nishanth E.; Kucejova, Blanka; Fu, Xiaorong; He, Tian Teng; Méndez-Lucas, Andrés; Shelton, John M.; Perales, Jose C.; Browning, Jeffrey D.; Burgess, Shawn C.

In: Journal of Lipid Research, Vol. 53, No. 6, 06.2012, p. 1080-1092.

Research output: Contribution to journalArticle

Satapati, Santhosh ; Sunny, Nishanth E. ; Kucejova, Blanka ; Fu, Xiaorong ; He, Tian Teng ; Méndez-Lucas, Andrés ; Shelton, John M. ; Perales, Jose C. ; Browning, Jeffrey D. ; Burgess, Shawn C. / Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. In: Journal of Lipid Research. 2012 ; Vol. 53, No. 6. pp. 1080-1092.
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