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This version published online on April 1, 2004
Endocrinology, doi:10.1210/en.2004-0260
A more recent version of this article appeared on July 1, 2004
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Submitted on March 1, 2004
Accepted on March 25, 2004

PPAR Activation induces tissue specific effects on fatty acid uptake and metabolism in vivo - A study using the novel PPAR {alpha} /{gamma} agonist Tesaglitazar

Bronwyn D Hegarty, Stuart M Furler*, Nicholas D Oakes, Edward W. Kraegen, and Gregory J Cooney

Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia; AstraZeneca R&D, Mölndal, Sweden.

* To whom correspondence should be addressed.

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 non-esterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly we examined the effect of the novel PPAR{alpha} /{gamma} agonist tesaglitazar on whole body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle (RG) and liver, in rats with dietary induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 weeks with or without treatment with tesaglitazar (1µmol.kg-1.day-1, 7 days). NEFA clearance was measured using the partially metabolizable NEFA tracer, 3H-R-bromopalmitate (3H-R-BrP), 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 CoAs (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 PPAR{alpha}/{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 PPAR {alpha} and PPAR {gamma} 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.
Key words: insulin resistance • PPAR • lipids • high-fat-fed rats




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