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

Abstract

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.

Figure 1

Effect of treatment with selective PPARα and PPARδ agonists on BW in lean and DIO AKR/J mice. (a) GW9578, a PPARα agonist (1 mg/kg), GW0742, a PPARδ agonist (30 mg/kg). (b) Filled triangle: GW9578 dosed for 14 days then combined with GW0742; filled diamond: GW0742 dosed for 14 days then combined with GW9578; filled square: GW9578 and GW0742 dosed together for 28 days. The arrow indicates the point at which the sequential combination of PPARα and PPARδ began. Data were analyzed by ANCOVA with repeated measures followed by Dunnett's post hoc test. Values were considered to be significant (*) when a value of P < .05 was achieved. N = 8–10 animals/group.

Figure 2

Effect of treatment with selective PPARα and PPARδ agonists on food consumption (kcal) in lean and DIO AKR/J mice. (a) GW9578, a PPARα agonist (1 mg/kg), GW0742, a PPARδ agonist (30 mg/kg). (b) Filled triangle: GW9578 dosed for 14 days then combined with GW0742; filled diamond: GW0742 dosed for 14 days then combined with GW9578; filled square: GW9578 and GW0742 dosed together for 28 days. The arrow indicates the point at which the sequential combination of PPARα and PPARδ began. Data were analyzed by ANCOVA with repeated measures followed by Dunnett's post hoc test. Values were considered to be significant (*) when a value of P < .05 was achieved. N = 8–10 animals/group.

Figure 3

Effect of treatment with rimonabant or selective PPARγ agonist on BW. (a) RIM (10 and 30 mg/kg). (b) GW7845, a selective PPARγ agonist (3 mg/kg). Data were analyzed by ANCOVA with repeated measures followed by Dunnett's post hoc test. Values were considered to be significant (*) when the value of P < .05 was achieved. N = 8–10 animals/group.

Figure 3

Effect of treatment with rimonabant or selective PPARγ agonist on BW. (a) RIM (10 and 30 mg/kg). (b) GW7845, a selective PPARγ agonist (3 mg/kg). Data were analyzed by ANCOVA with repeated measures followed by Dunnett's post hoc test. Values were considered to be significant (*) when the value of P < .05 was achieved. N = 8–10 animals/group.

Figure 4

Effect of treatment with rimonabant or selective PPARγ agonist on food consumption (kcal). (a) RIM (10 and 30 mg/kg). (b) GW7845, a selective PPARγ agonist (3 mg/kg). Data were analyzed by ANCOVA with repeated measures followed by Dunnett's post hoc test. Values were considered to be significant (*) when the value of P < .05 was achieved. N = 8–10 animals/group.

Figure 4

Effect of treatment with rimonabant or selective PPARγ agonist on food consumption (kcal). (a) RIM (10 and 30 mg/kg). (b) GW7845, a selective PPARγ agonist (3 mg/kg). Data were analyzed by ANCOVA with repeated measures followed by Dunnett's post hoc test. Values were considered to be significant (*) when the value of P < .05 was achieved. N = 8–10 animals/group.

Figure 5

Effect of treatment with PPARpan agonists on BW. (a) GW4148 dosed at 3 and 10 mg/kg. (b) GW9135 dosed at 3 and 10 mg/kg. Data are expressed as mean ± SEM and were analyzed by ANCOVA with repeated measures followed by Dunnett's post hoc test. Values were considered to be significant (*) when the value of P < .05 was achieved. N = 8 animals/group.

Figure 6

Effect of PPAR agonist treatment on fatty acid oxidation (FAO) in liver was assessed using a ¹⁴C capture method modified from Dohm et al. [28]. Data are expressed as fold change from vehicle control (mean ± SEM). N = 6 determinations/compound.