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Activation of PPAR promotes reversal of multiple metabolic abnormalities, reduces oxidative stress and increases fatty acid oxidation in moderately obese men

¹ OCDEM, University of Oxford, Oxford, UK
² GSK Discovery Medicine, CVU CEDD
³ GSK, Human Target Validation, CVU CEDD
⁴ GSK, statistics
⁵ GSK CPDM-CVU
⁶ GSK, ACCI, Cambridge, UK
⁷ Dept of Public Health, University of Uppsala, Uppsala, Sweden
⁸ Dept of Radiology, Churchill Hospital, University of Oxford, Oxford, UK
⁹ Wellcome Trust Clinical Research Facility, Addenbrooke's Hospital,
¹⁰ Cambridge, UK
¹¹ Dept of Clin Biochemistry and Medicine, University of Cambridge, UK
¹² GSK, Research Triangle Park, NC, USA
¹³ GSK, Stevenage, UK

Background: 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.

Methods: The PPAR agonist (GW501516, 10mg OD), a comparator PPAR agonist (GW590735, 20µg OD) and placebo were given in a double-blind, randomized, 3-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-hour 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%), apoB (-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) was 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.

Conclusion: 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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