Tesaglitazar, a dual PPAR α/γ agonist, ameliorates glucose and lipid intolerance in obese Zucker rats

Insulin impaired glucose tolerance, high circulating levels of free acids (FFA), and postprandial hyperlipidemia are associated with metabolic syndrome, which has been linked to increased risk of disease. We studied the metabolic responses to an oral triglyceride (TG) (1.7/2.0 g/kg lean body mass) load in three of conscious 7-h fasted Zucker rats: lean healthy controls, insulin-resistant/dyslipidemic controls, and obese rats treated the dual peroxisome proliferator-activated receptor alpha/gamma agonist, 3 mu mol(.)kg(-1.)day(-1) for 4 wk. Untreated obese Zucker displayed marked insulin resistance, as well as glucose and lipid in response to the glucose/TG load. The 2-h postload area the curve values were greater for glucose (+19%), insulin +849%), FFA (+53%), and TG (+413%) compared with untreated controls. Treatment with tesaglitazar lowered fasting plasma improved glucose tolerance, substantially reduced fasting postload insulin levels, and markedly lowered fasting TG and lipid tolerance. Fasting FFA were not affected, but postprandial FFA suppression was restored to levels seen in lean controls. of tesaglitazar- induced lowering of plasma TG were separately using the Triton WR1339 method. In anesthetized, h fasted, obese Zucker rats, tesaglitazar reduced hepatic TG secretion by 47%, increased plasma TG clearance by 490%, and reduced low-density lipoprotein (VLDL) apolipoprotein CIII content by compared with obese controls. In conclusion, the glucose/lipid test in obese Zucker rats appears to be a useful model of the syndrome that can be used to evaluate therapeutic effects on postprandial glucose and lipid metabolism. The present work that tesaglitazar ameliorates these abnormalities and insulin sensitivity in this animal model.