Differential Influences of Peroxisome Proliferator–Activated Receptorsγ and -α on Food Intake and Energy Homeostasis

Differential Influences of Peroxisome Proliferator–Activated Receptorsγ and -α on Food Intake and Energy Homeostasis Philip J. Larsen 1 2 , Per Bo Jensen 1 , Rikke V. Sørensen 1 , Leif Kongskov Larsen 1 , Niels Vrang 1 , Erik M. Wulff 3 and Karsten Wassermann 3 1 Rheoscience, Rødovre, Denmark 2 Center for Clinical and Basic Research, Ballerup, Denmark 3 Discovery Pharmacology, Novo Nordisk, Måløv, Denmark Address correspondence and reprint requests to Dr. Philip J. Larsen, Rheoscience, Glerupvej 2, 2610 Rødovre, Denmark. E-mail: pjl{at}rheoscience.com Abstract Chronic treatment with compounds activating peroxisome proliferator–activated receptor (PPAR)γ and -α influences body energy stores, but the underlying mechanisms are only partially known. In a chronic-dosing study, equiefficacious antihyperglycemic doses of the PPARγ agonist pioglitazone and PPARα/γ dual activator ragaglitazar were administered to obesity-prone male rats. The PPARα agonist fenofibrate had no effect on insulin sensitivity. Pioglitazone transiently increased and fenofibrate transiently decreased food intake, whereas ragaglitazar had no impact on feeding. As a result, body adiposity increased in pioglitazone-treated rats and decreased in fenofibrate-treated rats. PPARγ compounds markedly increased feed efficiency, whereas PPARα agonist treatment decreased feed efficiency. In fenofibrate-treated rats, plasma acetoacetate was significantly elevated. Plasma levels of this potentially anorectic ketone body were unaffected in pioglitazone- and ragaglitazar-treated rats. High-fat feeding markedly increased visceral fat pads, and this was prevented by pioglitazone and ragaglitazar treatment. Pioglitazone treatment enlarged subcutaneous adiposity in high-fat–fed rats. In conclusion, PPARγ activation increases both food intake and feed efficiency, resulting in net accumulation of subcutaneous body fat. The impact of PPARγ activation on feeding and feed efficiency appears to be partially independent because the PPARα component of ragaglitazar completely counteracts the orexigenic actions of PPARγ activation without marked impact on feed efficiency. LPL, lipoprotein lipase OGTT, oral glucose tolerance test PPAR, peroxisome proliferator–activated receptor UCP-1, uncoupling protein-1 Footnotes Accepted June 10, 2003. Received May 5, 2003. DIABETES