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J. Biol. Chem., Vol. 277, Issue 50, 48501-48507, December 13, 2002
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From the a Department of Laboratory Medicine, University
of California, San Francisco, California 94143; b Institute
for Clinical and Experimental Medicine, 14220 Prague, Czech Republic
14220; c Institute of Physiology, Czech Academy of Sciences,
and Center for Integrated Genomics 14220, Prague, Czech Republic;
d Institutes of Molecular Genetics and Physiology, Czech
Academy of Sciences 14220, Prague, Czech Republic;
e Institute of Biology & Medical Genetics, First Medical
Faculty, Charles University, Prague, Czech Republic;
f Department of Family Medicine, University of California,
Irvine and Kern Medical Center, Bakersfield, California 93305;
g Department of Veterans Affairs Medical Center, San
Francisco, California 94143; i Department of Physiology and
Biophysics, State University of New York, Stony Brook, New York
11794
Pioglitazone, like other
thiazolidinediones, is an insulin-sensitizing agent that activates the
peroxisome proliferator-activated receptor
Pharmacogenetic Evidence That Cd36 Is a Key
Determinant of the Metabolic Effects of Pioglitazone*
and influences
the expression of multiple genes involved in carbohydrate and lipid
metabolism. However, it is unknown which of these many target genes
play primary roles in determining the antidiabetic and hypolipidemic
effects of thiazolidinediones. To specifically investigate the role of
the Cd36 fatty acid transporter gene in the
insulin-sensitizing actions of thiazolidinediones, we studied the
metabolic effects of pioglitazone in spontaneously hypertensive rats
(SHR) that harbor a deletion mutation in Cd36 in comparison
to congenic and transgenic strains of SHR that express wild-type
Cd36. In congenic and transgenic SHR with wild-type Cd36, administration of pioglitazone was associated with
significantly lower circulating levels of fatty acids, triglycerides,
and insulin as well as lower hepatic triglyceride levels and epididymal
fat pad weights than in SHR harboring mutant Cd36.
Additionally, insulin-stimulated glucose oxidation in isolated soleus
muscle was significantly augmented in pioglitazone-fed rats with
wild-type Cd36 versus those with mutant
Cd36. The Cd36 genotype had no effect on
pioglitazone-induced changes in blood pressure. These findings provide
direct pharmacogenetic evidence that in the SHR model, Cd36
is a key determinant of the insulin-sensitizing actions of a
thiazolidinedione ligand of peroxisome proliferator-activated receptor
.
*
This work was partially supported by Grants 301/00/1636 and
204/98/K015 from the Grant Agency of the Czech Republic (to V. Z. and
M. P.), Research Project AVOZ5011922 to the Institute of Physiology,
National Institutes of Health Grants RO1 HL56028 and PO1 HL35018
(Project 2) and RO3 TW01236 (to T. K.) and RO1 HL63709 (to
E. S. L.), and Grant 6367-3 from the Internal Grant Agency of the
Ministry of Health of the Czech Republic (to L.K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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