MALONYL COENZYME-A AND ADIPOSITY IN THE DAHL SALT-SENSITIVE RAT - EFFECTS OF PIOGLITAZONE

These studies were designed to assess the effects of pioglitazone, a n ew oral antidiabetic agent that acts by improving insulin sensitivity, on blood pressure, plasma and tissue lipids, and insulin resistance i n the Dahl salt-sensitive (Dahl-S) rat. Reaven et al had reported that male Dahl-S rats are moderately hyperinsulinemic and insulin-resistan t. This was of particular interest since these rats are not obese but are hypertriglyceridemic. and on a high-salt diet they become hyperten sive. In the current study, male Sprague-Dawley control and Dahl-S rat s were compared when fed standard chow or high-fat, high-sucrose (HFHS ) diets with or without pioglitazone (20 mg/kg body weight/d) for 3 we eks. On the standard chow diet, Dahl-S rats were hypertriglyceridemic and had high tissue levels of malonyl coenzyme A ([CoA] Dahl-S 5.0 v c ontrol 3.3 nmol/g in muscle, and Dahl-S 15.6 v control 10.7 nmol/g in liver); however, they were not hyperinsulinemic. Pioglitazone therapy decreased both malonyl CoA and plasma triglycerides toward control val ues, but had no effect on plasma insulin levels. On the HFHS diet, bot h groups became glucose-intolerant and hyperinsulinemic; however, the hyperinsulinemia was greater and more sustained in Dahl-S rats. In add ition, the HFHS diet appeared to increase the mass of retroperitoneal fat in the Dahl-S but not in the control group. Treatment with pioglit azone decreased retroperitoneal fat, but as reported previously, it in creased the mass of the epididymal fat pad. The results suggest that t he hypertriglyceridemia of the Dahl-S rat is associated with an increa se in the concentration of malonyl CoA in both liver and muscle. They also show that pioglitazone reverses both of these abnormalities indep endently of its effect on plasma insulin. Whether these high levels of malonyl CoA predispose the Dahl-S rat to hyperinsulinemia and possibl y obesity when placed on a HFHS diet remains to be determined. (C) 199 6 by W.B. Saunders Company