The Effect of PPARα, PPARδ, PPARγ, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice

Activation of peroxisome proliferator-activated receptor (PPAR) α , δ , and γ subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. PPARpan agonists which activate all three receptor subtypes have antidiabetic activity in animal models without the weight gain associated with selective PPAR γ agonists. Herein we report the effects of selective PPAR agonists (GW9578, a PPAR α agonist, GW0742, a PPAR δ agonist, GW7845, a PPAR γ agonist), combination of PPAR α and δ agonists, and PPARpan (PPAR α / γ / δ ) activators (GW4148 or GW9135) on body weight (BW), body composition, food consumption, fatty acid oxidation, and serum chemistry of diet-induced obese AKR/J mice. PPAR α or PPAR δ agonist treatment induced a slight decrease in fat mass (FM) while a PPAR γ agonist increased BW and FM commensurate with increased food consumption. The reduction in BW and food intake after cotreatment with PPAR α and δ agonists appeared to be synergistic. GW4148, a PPARpan agonist, induced a significant and sustained reduction in BW and FM similar to an efficacious dose of rimonabant, an antiobesity compound. GW9135, a PPARpan agonist with weak activity at PPAR δ , induced weight loss initially followed by rebound weight gain reaching vehicle control levels by the end of the experiment. We conclude that PPAR α and PPAR δ activations are critical to effective weight loss induction. These results suggest that the PPARpan compounds may be expected to maintain the beneficial insulin sensitization effects of a PPAR γ agonist while either maintaining weight or producing weight loss.