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Diabetes Publish Ahead of Print published online ahead of print May 9, 2008
DOI: 10.2337/db08-0226
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Original Research

Partial resistance to PPAR{alpha} agonists in Zucker diabetic fatty (ZDF) rats is associated with defective hepatic mitochondrial metabolism

Santhosh Satapati, MS1,,5, TianTeng He, MD1, Takeshi Inagaki, MD3, Matthew Potthoff, PhD3, Matthew E. Merritt, PhD1, Victoria Esser, MD2, David J. Mangelsdorf, PhD3, Steven A. Kliewer, PhD3,,4, Jeffrey D. Browning, PhD1,,2, and Shawn C. Burgess, PhD1,,3,,5

1The Advanced Imaging Research Center
2Department of Internal Medicine
3Department of Pharmacology, and Howard Hughes Medical Institute
4Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX
5Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX

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 if abnormal mitochondrial metabolism might play 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 (NMR) spectroscopy in Zucker Diabetic Fatty (ZDF) rats during early and advanced diabetes. To determine whether defects in hepatic fat oxidation can be corrected by PPAR{alpha} activation, rats were treated with WY14,643 for 3-weeks prior to tracer administration.

Results: Hepatic mitochondrial fat oxidation in the diabetic liver was impaired 2-fold secondary to decreased ketogenesis, but 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 over-stimulated 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 co-dependence 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.

Correspondence: shawn.burgess{at}utsouthwestern.edu


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