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

Abstract

Background: Pharmacological use of peroxisome proliferator-activated receptor-δ (PPARδ) agonists, and transgenic overexpression of PPARδ 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 PPARδ agonist (GW501516, 10mg OD), a comparator PPARα 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 PPARδ 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.