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Diabetes 57:332-339, 2008
DOI: 10.2337/db07-1318
© 2008 by the American Diabetes Association
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Activation of Peroxisome Proliferator–Activated Receptor (PPAR)
Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men
1 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
2 Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania
3 Human Target Validation, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania
4 Statistics, GlaxoSmithKline, King of Prussia, Pennsylvania
5 Clinical Pharmacology and Discovery Medicine/Cardiovascular and Urogenital (CPDM CVU) Unit, GlaxoSmithKline, King of Prussia, Pennsylvania
6 Addenbrooke's Centre for Clinical Investigation (ACCI) Unit, GlaxoSmithKline, Cambridge, U.K
7 Department of Public Health, University of Uppsala, Uppsala, Sweden
8 Department of Radiology, Churchill Hospital, University of Oxford, Oxford, U.K
9 Wellcome Trust Clinical Research Facility, Addenbrooke's Hospital, Cambridge, U.K
10 Department of Clinical Biochemistry and Medicine, University of Cambridge, Cambridge, U.K
11 GlaxoSmithKline, Research Triangle Park, North Carolina
12 GlaxoSmithKline, Stevenage, U.K
Address correspondence and reprint requests to Dr. F. Karpe, Churchill Hospital, Oxford OX3 7LJ, U.K. E-mail: fredrik.karpe{at}ocdem.ox.ac.uk
Abbreviations:
Apo, apolipoprotein; AST, aspartate aminotransferase; AUC, area under the curve; 
GT, -glutamyltransferase; LCM, laser capture microdissection; LPL, lipoprotein lipase; MRI, magnetic resonance imaging; NEFA, nonesterified fatty acid; TTR, tracer-to-tracee ratio
OBJECTIVE— Pharmacological use of peroxisome proliferator–activated receptor (PPAR)
agonists and transgenic overexpression of PPAR in mice suggest amelioration of features of the metabolic syndrome through enhanced fat oxidation in skeletal muscle. We hypothesize a similar mechanism operates in humans.
RESEARCH DESIGN AND METHODS— The PPAR agonist (10 mg o.d. GW501516), a comparator PPAR
agonist (20 µg o.d. GW590735), and placebo were given in a double-blind, randomized, three-parallel group, 2-week study to six healthy moderately overweight subjects in each group. Metabolic evaluation was made before and after treatment including liver fat quantification, fasting blood samples, a 6-h meal tolerance test with stable isotope fatty acids, skeletal muscle biopsy for gene expression, and urinary isoprostanes for global oxidative stress.
RESULTS— Treatment with GW501516 showed statistically significant reductions in fasting plasma triglycerides (–30%), apolipoprotein B (–26%), LDL cholesterol (–23%), and insulin (–11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content (P < 0.05) and 30% reduction in urinary isoprostanes (P = 0.01) were also observed. Except for a lowering of triglycerides (–30%, P < 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO2 directly originating from the fat content of the meal was increased (P < 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b (CPT1b) was also significantly increased.
CONCLUSIONS— The PPAR agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle.
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