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

Diabetes. 2008 Aug;57(8):2012-21. doi: 10.2337/db08-0226. Epub 2008 May 9.


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 (2)H/(13)C 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-)-alpha 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 carboxylase flux were normal in newly diabetic rats and elevated in older rats. Treatment of diabetic rats with a PPAR-alpha 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-alpha 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-alpha agonists on glycemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Fatty Acids, Nonesterified / blood
  • Gluconeogenesis
  • Glucose / metabolism
  • Insulin / blood
  • Lipid Metabolism / drug effects
  • Liver / drug effects
  • Liver / metabolism*
  • Magnetic Resonance Spectroscopy
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • PPAR alpha / agonists*
  • Pyrimidines / pharmacology*
  • Radioimmunoassay
  • Rats
  • Rats, Zucker
  • Triglycerides / blood


  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Insulin
  • PPAR alpha
  • Pyrimidines
  • Triglycerides
  • pirinixic acid
  • Glucose