title: Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men.
abstract: 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.
  
  
  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.affiliation: Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Ulf
authors.initials: U
authors.lastname: Risérus
authors.forename: Dennis
authors.initials: D
authors.lastname: Sprecher
authors.forename: Tony
authors.initials: T
authors.lastname: Johnson
authors.forename: Eric
authors.initials: E
authors.lastname: Olson
authors.forename: Sandra
authors.initials: S
authors.lastname: Hirschberg
authors.forename: Aixue
authors.initials: A
authors.lastname: Liu
authors.forename: Zeke
authors.initials: Z
authors.lastname: Fang
authors.forename: Priti
authors.initials: P
authors.lastname: Hegde
authors.forename: Duncan
authors.initials: D
authors.lastname: Richards
authors.forename: Leli
authors.initials: L
authors.lastname: Sarov-Blat
authors.forename: Jay C
authors.initials: JC
authors.lastname: Strum
authors.forename: Samar
authors.initials: S
authors.lastname: Basu
authors.forename: Jane
authors.initials: J
authors.lastname: Cheeseman
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Fielding
authors.forename: Sandy M
authors.initials: SM
authors.lastname: Humphreys
authors.forename: Theodore
authors.initials: T
authors.lastname: Danoff
authors.forename: Niall R
authors.initials: NR
authors.lastname: Moore
authors.forename: Peter
authors.initials: P
authors.lastname: Murgatroyd
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Pauline
authors.initials: P
authors.lastname: Sutton
authors.forename: Tim
authors.initials: T
authors.lastname: Willson
authors.forename: David
authors.initials: D
authors.lastname: Hassall
authors.forename: Keith N
authors.initials: KN
authors.lastname: Frayn
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
mesh_terms: D000293:Adolescent; D000328:Adult; D001055:Apolipoproteins B / Q000097:blood / Q000187:drug effects; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects; D004311:Double-Blind Method; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000503:physiopathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D047494:PPAR delta / Q000819:agonists / Q000502:physiology*; D010919:Placebos; D013844:Thiazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D005227:Fatty Acids; C425931:GW 501516; D047494:PPAR delta; D010919:Placebos; D013844:Thiazoles; D014280:Triglycerides