Document Detail


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.
MedLine Citation:
PMID:  18024853     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2007-11-16
Journal Detail:
Title:  Diabetes     Volume:  57     ISSN:  1939-327X     ISO Abbreviation:  Diabetes     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-01-29     Completed Date:  2008-03-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  United States    
Other Details:
Languages:  eng     Pagination:  332-9     Citation Subset:  AIM; IM    
Affiliation:
Churchill Hospital, Oxford OX3 7LJ, UK.
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MeSH Terms
Descriptor/Qualifier:
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
Chemical
Reg. No./Substance:
0/Apolipoproteins B; 0/Cholesterol, HDL; 0/Fatty Acids; 0/GW 501516; 0/PPAR delta; 0/Placebos; 0/Thiazoles; 0/Triglycerides

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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