JTT-501, a new oral hypoglycemic agent, reverses hypertriglyceridemia in Zucker fatty and ventromedial hypothalamus-lesioned obese rats

JTT-501 is a new oral hypoglycemic agent that is reported to be effective in insulin-resistant diabetic animal models by improving insulin resistance. It also improves hypertriglyceridemia. We investigated the mechanism of the reversal of hypertriglyceridemia in two types of obese animals using JTT-501. In Zucker fatty obese rats, an animal model of genetic obesity, fasting plasma triglyceride and glucose significantly decreased after a single daily oral dose of JTT-501 (100 mg/kg) for 7 days. In ventromedial hypothalamus (VMH)-lesioned obese rats, an animal model of nongenetic obesity, fasting plasma triglycerides significantly decreased but fasting plasma glucose levels remained unchanged after treatment with this agent. In Sprague-Dawley (SD) rats, fasting plasma triglyceride and glucose levels remained unchanged. The JTT-501-treated Zucker fatty and VMH-lesioned obese rats showed a decrease in insulin, but it was not significant, while the treated SD rats showed a significant decrease in insulin. Postheparin plasma lipoprotein lipase (LPL) increased significantly in treated Zucker fatty obese and SD rats, but did not change in VMH-lesioned obese rats. The hepatic triglyceride secretion rate (TGSR) did not change in any species treated with JTT-501. There was a negative correlation between postheparin plasma LPL and plasma triglyceride levels in Zucker fatty obese rats, while no such correlation was observed in VMH-lesioned obese or SD rats. The fractional catabolic rate (FCR) for plasma triglyceride was increased significantly by JTT-501 in both Zucker fatty and VMH-lesioned obese rats. These results suggest that JTT-501 decreases plasma triglycerides mainly by increasing postheparin plasma LPL in Zucker fatty obese rats, while it ameliorates an impairment in the ability of adipose tissue to remove triglyceride from the circulation in VMH-lesioned obese rats.