Journal article
Partial Resistance to Peroxisome Proliferator–Activated Receptor-α Agonists in ZDF Rats Is Associated With Defective Hepatic Mitochondrial Metabolism
Diabetes (New York, N.Y.), Vol.57(8), pp.2012-2021
08/2008
DOI: 10.2337/db08-0226
PMCID: PMC2494699
PMID: 18469201
Abstract
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-)-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 carboxylase 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-α 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.
Details
- Title: Subtitle
- Partial Resistance to Peroxisome Proliferator–Activated Receptor-α Agonists in ZDF Rats Is Associated With Defective Hepatic Mitochondrial Metabolism
- Creators
- Santhosh Satapati - The Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TexasTianTeng He - The Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TexasTakeshi Inagaki - Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TexasMatthew Potthoff - Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TexasMatthew E Merritt - The Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TexasVictoria Esser - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasDavid J Mangelsdorf - Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TexasSteven A Kliewer - Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TexasJeffrey D Browning - The Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TexasShawn C Burgess - The Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.57(8), pp.2012-2021
- DOI
- 10.2337/db08-0226
- PMID
- 18469201
- PMCID
- PMC2494699
- NLM abbreviation
- Diabetes
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Publisher
- American Diabetes Association
- Language
- English
- Date published
- 08/2008
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984040539202771
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