Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight

Activators of peroxisome proliferator activated receptors (PPARs) are effec tive drugs to improve the metabolic abnormalities linking hypertriglyceride mia to diabetes, hyperglycemia, insulin-resistance, and atherosclerosis. We compared the pharmacological profile of a PPAR alpha activator, fenofibrat e, and a PPAR gamma activator, rosiglitazone, on serum parameters, target g ene expression, and body weight gain in (fa/fa) fatty Zucker rats and db/db mice as well as their association in db/db mice. Fenofibrate faithfully mo dified the expression of PPAR alpha responsive genes. Rosiglitazone increas ed adipose tissue aP2 mRNA in both models while increasing liver acyl CoA o xidase mRNA in db/db mice but not in fatty Zucker rats. Both drugs lowered serum triglycerides yet rosiglitazone markedly increased body weight gain w hile fenofibrate decreased body weight gain in fatty Zucker rats. KRP 297, which has been reported to be a PPAR alpha and gamma co-activator, also aff ected serum triglycerides and insulin in fatty Zucker rats although no chan ge in body weight gain was noted. These results serve to clearly differenti ate the metabolic finality of two distinct classes of drugs, as well as the ir corresponding nuclear receptors, having similar effects on serum triglyc erides. (C) 2000 Academic Press.