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.

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: Ulf Risérus, Dennis Sprecher, Tony Johnson, Eric Olson, Sandra Hirschberg, Aixue Liu, Zeke Fang, Priti Hegde, Duncan Richards, Leli Sarov-Blat, Jay C Strum, Samar Basu, Jane Cheeseman, Barbara A Fielding, Sandy M Humphreys, Theodore Danoff, Niall R Moore, Peter Murgatroyd, Stephen O'Rahilly, Pauline Sutton, Tim Willson, David Hassall, Keith N Frayn, Fredrik Karpe
• Journal: Diabetes (Diabetes) Vol. 57 Issue 2 Pg. 332-9 (Feb 2008) ISSN: 1939-327X [Electronic] United States
• PMID: 18024853 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins B
• Cholesterol, HDL
• Fatty Acids
• GW 501516
• PPAR delta
• Placebos
• Thiazoles
• Triglycerides

Topics

• Adolescent
• Adult
• Apolipoproteins B (blood, drug effects)
• Cholesterol, HDL (blood, drug effects)
• Double-Blind Method
• Fatty Acids (metabolism)
• Humans
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Obesity (physiopathology)
• Oxidation-Reduction
• Oxidative Stress (physiology)
• PPAR delta (agonists, physiology)
• Placebos
• Thiazoles (pharmacology)
• Triglycerides (blood)