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 micromol.kg(-1).d(-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.