PPARalpha /gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly

1 Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia; 2 Rheoscience, DK-2100 Copenhagen; and 3 Novo Nordisk, DK-2760 Måløv, Denmark Peroxisome proliferator-activated receptor (PPAR) and PPAR agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPAR / agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPAR agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPAR agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P