OBJECTIVE: Pharmacological use of peroxisome proliferator-activated receptor (PPAR)delta agonists and transgenic overexpression of PPARdelta 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 PPARdelta agonist (10 mg o.d. GW501516), a comparator PPARalpha agonist (20 mug 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 CO(2) 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 PPARdelta 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.
RCT Entities:
OBJECTIVE: Pharmacological use of peroxisome proliferator-activated receptor (PPAR)delta agonists and transgenic overexpression of PPARdelta 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 PPARdelta agonist (10 mg o.d. GW501516), a comparator PPARalpha agonist (20 mug 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 CO(2) 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 PPARdelta 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.
Authors: Xiangsheng Zuo; Min Xu; Jiang Yu; Yuanqing Wu; Micheline J Moussalli; Ganiraju C Manyam; Sun Il Lee; Shoudan Liang; Mihai Gagea; Jeffrey S Morris; Russell R Broaddus; Imad Shureiqi Journal: J Natl Cancer Inst Date: 2014-03-28 Impact factor: 13.506
Authors: Andres V Ardisson Korat; Vasanti S Malik; Jeremy D Furtado; Frank Sacks; Bernard Rosner; Kathryn M Rexrode; Walter C Willett; Dariush Mozaffarian; Frank B Hu; Qi Sun Journal: J Nutr Date: 2020-02-01 Impact factor: 4.798
Authors: José Iglesias; Sebastian Barg; David Vallois; Shawon Lahiri; Catherine Roger; Akadiri Yessoufou; Sylvain Pradevand; Angela McDonald; Claire Bonal; Frank Reimann; Fiona Gribble; Marie-Bernard Debril; Daniel Metzger; Pierre Chambon; Pedro Herrera; Guy A Rutter; Marc Prentki; Bernard Thorens; Walter Wahli Journal: J Clin Invest Date: 2012-10-24 Impact factor: 14.808