Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity

Fibrates and glitazones are two classes of drugs currently used in the trea tment of dyslipidemia and insulin resistance (IR), respectively. Whereas gl itazones are insulin sensitizers acting via activation of the peroxisome pr oliferator-activated receptor (PPAR) gamma subtype, fibrates exert their li pid-lowering activity via PPAR alpha. To determine whether PPAR alpha activ ators also improve insulin sensitivity, we measured the capacity of three P PAR alpha-selective agonists, fenofibrate, ciprofibrate, and the new compou nd GW9578, in two rodent models of high fat diet-induced (C57BL/6 mice) or genetic (obese Zucker rats) IR. At doses yielding serum concentrations show n to activate selectively PPAR alpha, these compounds markedly lowered hype rinsulinemia and, when present, hyperglycemia in both animal models. This e ffect relied on the improvement of insulin action on glucose utilization, a s indicated by a lower insulin peak in response to intraperitoneal glucose in ciprofibrate-treated IR obese Zucker rats. In addition, fenofibrate trea tment prevented high fat diet-induced increase of body weight and adipose t issue mass without influencing caloric intake. The specificity for PPAR alp ha activation in vivo was demonstrated by marked alterations in the express ion of PPAR alpha target genes, whereas PPAR gamma target gene mRNA levels did not change in treated animals. These results indicate that compounds wi th a selective PPAR alpha activation profile reduce insulin resistance with out having adverse effects on body weight and adipose tissue mass in animal models of IR.