OBJECTIVE-Pharmacological use of peroxisome proliferatoractivated 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, 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 GW501516showed statistically significant reductions in fasting plasma triglycerides (Ϫ30%), apolipoprotein B (Ϫ26%), LDL cholesterol (Ϫ23%), and insulin (Ϫ11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content (P Ͻ 0.05) and 30% reduction in urinary isoprostanes (P ϭ 0.01) were also observed. Except for a lowering of triglycerides (Ϫ30%, P Ͻ 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO 2 directly originating from the fat content of the meal was increased (P Ͻ 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. Diabetes 57: 332-339, 2008

Peroxisome proliferator-activated receptor (PPAR) b-null mice exhibit exacerbated epithelial cell proliferation and enhanced sensitivity to skin carcinogenesis, suggesting that ligand activation of PPARb will inhibit keratinocyte proliferation. By using of a highly specific ligand (GW0742) and the PPARb-null mouse model, activation of PPARb was found to selectively induce keratinocyte terminal differentiation and inhibit keratinocyte proliferation. Additionally, GW0742 was found to be anti-inflammatory due to inhibition of myeloperoxidase activity, independent of PPARb. These data suggest that ligand activation of PPARb could be a novel approach to selectively induce differentiation and inhibit cell proliferation, thus representing a new molecular target for the treatment of skin disorders resulting from altered cell proliferation such as psoriasis and cancer.

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