The PPARα/γ Agonist, Tesaglitazar, Improves Insulin Mediated Switching of Tissue Glucose and Free Fatty Acid Utilization In Vivo in the Obese Zucker Rat

Metabolic flexibility was assessed in male Zucker rats: lean controls, obese controls, and obese rats treated with the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist, tesaglitazar, 3 mu mol/kg/day for 3 weeks. Whole body glucose disposal rate (R-d) and hepatic glucose output (HGO) were assessed under basal fasting and hyperinsulinemic isoglycemic clamp conditions using [3,H-3] glucose. Indices of tissue specific glucose utilization (R-g') were measured at basal, physiological, and supraphysiological levels of insulinemia using 2-deoxy-D-[2,6-H-3]glucose. Finally, whole body and tissue specific FFA and glucose utilization and metabolic fate were evaluated under basal and hyperinsulinemic conditions using a combination of [U-C-13]glucose, 2-deoxy-D-[U-C-14]glucose, [U-C-14]palmitate, and [9,10-H-3]-(R)-bromopalmitate. Tesaglitazar improved whole body insulin action by greater suppression of HGO and stimulation of R-d compared to obese controls. This involved increased insulin stimulation of R-g' in fat and skeletal muscle as well as increased glycogen synthesis. Tesaglitazar dramatically improved insulin mediated suppression of plasma FFA level, whole body turnover (R-fa), and muscle, liver, and fat utilization. At basal insulin levels, tesaglitazar failed to lower HGO or R-fa compared to obese controls. In conclusion, the results demonstrate that tesaglitazar has a remarkable ability to improve insulin mediated control of glucose and FFA fluxes in obese Zucker rats.