The Effect of PPARalpha, PPARdelta, PPARgamma, 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) alpha, delta, and gamma 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 PPARgamma agonists. Herein we report the effects of selective PPAR agonists (GW9578, a PPARalpha agonist, GW0742, a PPARdelta agonist, GW7845, a PPARgamma agonist), combination of PPARalpha and delta agonists, and PPARpan (PPARalpha/gamma/delta) 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. PPARalpha or PPARdelta agonist treatment induced a slight decrease in fat mass (FM) while a PPARgamma agonist increased BW and FM commensurate with increased food consumption. The reduction in BW and food intake after cotreatment with PPARalpha and delta 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 PPARdelta, induced weight loss initially followed by rebound weight gain reaching vehicle control levels by the end of the experiment. We conclude that PPARalpha and PPARdelta 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 PPARgamma agonist while either maintaining weight or producing weight loss.
Harrington
W Wallace
WW
Department of Metabolic Diseases, GlaxoSmithKline Research, Research Triangle Park, NC 27709, USA.
S Britt
Christy
C
G Wilson
Joan
J
O Milliken
Naphtali
N
G Binz
Jane
J
C Lobe
David
D
R Oliver
William
W
C Lewis
Michael
M
M Ignar
Diane
D
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