Partial resistance to peroxisome proliferator-activated receptor-α agonists in ZDF rats is associated with defective hepatic mitochondrial metabolism

Santhosh Satapati, Tianteng He, Takeshi Inagaki, Matthew Potthoff, Matthew E. Merritt, Victoria Esser, David J. Mangelsdorf, Steven A. Kliewer, Jeffrey D. Browning, Shawn C. Burgess

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38 Scopus citations


OBJECTIVE-Fluxes through mitochondrial pathways are defective in insulin-resistant skeletal muscle, but it is unclear whether similar mitochondrial defects play a role in the liver during insulin resistance and/or diabetes. The purpose of this study is to determine whether abnormal mitochondrial metabolism plays a role in the dysregulation of both hepatic fat and glucose metabolism during diabetes. RESEARCH DESIGN AND METHODS- Mitochondrial fluxes were measured using 2H/ 13C tracers and nuclear magnetic resonance spectroscopy in ZDF rats during early and advanced diabetes. To determine whether defects in hepatic fat oxidation can be corrected by peroxisome proliferator-activated receptor (PPAR-)-α activation, rats were treated with WY14,643 for 3 weeks before tracer administration. RESULTS-Hepatic mitochondrial fat oxidation in the diabetic liver was impaired twofold secondary to decreased ketogenesis, but tricarboxylic acid (TCA) cycle activity and pyruvate carbox- ylase flux were normal in newly diabetic rats and elevated in older rats. Treatment of diabetic rats with a PPAR-α agonist induced hepatic fat oxidation via ketogenesis and hepatic TCA cycle activity but failed to lower fasting glycemia or endogenous glucose production. In fact, PPAR-a agonism overstimulated mitochondrial TCA cycle flux and induced pyruvate carboxylase flux and gluconeogenesis in lean rats. CONCLUSIONS-The impairment of certain mitochondrial fluxes, but preservation or induction of others, suggests a complex defect in mitochondrial metabolism in the diabetic liver. These data indicate an important codependence between hepatic fat oxidation and gluconeogenesis in the normal and diabetic state and potentially explain the sometimes equivocal effect of PPAR-α agonists on glycemia.

Original languageEnglish (US)
Pages (from-to)2012-2021
Number of pages10
Issue number8
StatePublished - Aug 1 2008


ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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