Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Diabetes. 2008 Feb;57(2):332-9. Epub 2007 Nov 16.

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.

Author information

  • 1Churchill Hospital, Oxford OX3 7LJ, UK.

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.

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.

PMID:
18024853
[PubMed - indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for HighWire
    Loading ...
    Write to the Help Desk