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.
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.
Risérus
Ulf
U
Churchill Hospital, Oxford OX3 7LJ, UK.
Sprecher
Dennis
D
Johnson
Tony
T
Olson
Eric
E
Hirschberg
Sandra
S
Liu
Aixue
A
Fang
Zeke
Z
Hegde
Priti
P
Richards
Duncan
D
Sarov-Blat
Leli
L
Strum
Jay C
JC
Basu
Samar
S
Cheeseman
Jane
J
Fielding
Barbara A
BA
Humphreys
Sandy M
SM
Danoff
Theodore
T
Moore
Niall R
NR
Murgatroyd
Peter
P
O'Rahilly
Stephen
S
Sutton
Pauline
P
Willson
Tim
T
Hassall
David
D
Frayn
Keith N
KN
Karpe
Fredrik
F
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
D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D005227:Fatty Acids; C425931:GW 501516; D047494:PPAR delta; D010919:Placebos; D013844:Thiazoles; D014280:Triglycerides