Document Detail

Peroxisome proliferator-activated receptor (PPAR) activation induces tissue-specific effects on fatty acid uptake and metabolism in vivo--a study using the novel PPARalpha/gamma agonist tesaglitazar.
MedLine Citation:
PMID:  15059948     Owner:  NLM     Status:  MEDLINE    
Agonists of peroxisome proliferator-activated receptors (PPARs) have emerged as important pharmacological agents for improving insulin action. A major mechanism of action of PPAR agonists is thought to involve the alteration of the tissue distribution of nonesterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly, we examined the effect of the novel PPARalpha/gamma agonist tesaglitazar on whole-body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle, and liver in rats with dietary-induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 wk with or without treatment with tesaglitazar (1, 7 d). NEFA clearance was measured using the partially metabolizable NEFA tracer, (3)H-R-bromopalmitate, administered under conditions of basal or elevated NEFA availability. Tesaglitazar improved the insulin sensitivity of high-fat-fed rats, indicated by an increase in the glucose infusion rate during hyperinsulinemic-euglycemic clamp (P < 0.01). This improvement in insulin action was associated with decreased diglyceride (P < 0.05) and long chain acyl coenzyme A (P < 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P < 0.001). In addition the PPARalpha/gamma agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P < 0.05). This study shows that tesaglitazar is an effective insulin-sensitizing agent in a mild dietary model of insulin resistance. Furthermore, we provide the first direct in vivo evidence that an agonist of both PPARalpha and PPARgamma increases the ability of WAT, liver, and skeletal muscle to use fatty acids in association with its beneficial effects on insulin action in this model.
Bronwyn D Hegarty; Stuart M Furler; Nicholas D Oakes; Edward W Kraegen; Gregory J Cooney
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-04-01
Journal Detail:
Title:  Endocrinology     Volume:  145     ISSN:  0013-7227     ISO Abbreviation:  Endocrinology     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-06-16     Completed Date:  2004-07-14     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3158-64     Citation Subset:  AIM; IM    
Diabetes and Obesity Research Program, The Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.
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MeSH Terms
Adipose Tissue / drug effects,  metabolism
Cinnamates / pharmacology*
Dietary Fats / pharmacokinetics
Fatty Acids, Nonesterified / metabolism*
Insulin / metabolism
Insulin Resistance
Liver / drug effects,  metabolism
Muscle, Skeletal / drug effects,  metabolism*
Rats, Wistar
Receptors, Cytoplasmic and Nuclear / agonists*,  metabolism*
Transcription Factors / agonists*,  metabolism*
Reg. No./Substance:
0/(S)-2-ethoxy-3-(4-(2-(4-methylsulphonyloxyphenyl)ethoxy)phenyl)propanoic acid; 0/Cinnamates; 0/Dietary Fats; 0/Fatty Acids, Nonesterified; 0/Receptors, Cytoplasmic and Nuclear; 0/Transcription Factors; 11061-68-0/Insulin

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