Effects of GPR18 Ligands on Body Weight and Metabolic Parameters in a Female Rat Model of Excessive Eating

Abstract

GPR18 has been proposed to play a role in the progression of metabolic disease and obesity. Therefore, the aim of this study was to determine the effects of selective GRP18 ligands (the antagonists PSB-CB5 and PSB-CB27 and the agonist PSB-KK1415) on body mass and the development of metabolic disorders commonly accompanying obesity. Experiments were carried out on female Wistar rats. In order to determine the anorectic activity of the investigated ligands, their effect on food and water intake in a model of excessive eating was assessed. Lipid profile, glucose and insulin levels as well as alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activity in plasma were also evaluated. Potential side effects were examined in rat models of pica behavior and conditioned taste aversion. Animals treated with different ligands gained significantly less weight than rats from the obese control group. Effects of GPR18 antagonists on food intake and body weight were specific and unrelated to visceral illness, stress or changes in spontaneous activity. However, the GPR18 agonist is likely to affect body weight by inducing gastrointestinal disorders such as nausea. The presented preliminary data support the idea that the search for selective GPR18 antagonists for the treatment of obesity might be promising.

Keywords: GPR18 ligands; PSB-CB5; anorectic activity; excessive eating model; palatable diet.

Figure 1

Effect of diet or long-term administration of the GPR18 ligands or rimonabant, on body weight of female Wistar rats in the model of excessive eating. (A) Sum of body weight changes. (B) Changes of body weight in individual weeks. Result are means ± SEM, n = 6. Multiple comparison against the vehicle-treated control group (*) or against the vehicle-treated obese control group (^) or against the vehicle-treated obese control group in second week (#) or against the PSB-KK1415-treated group in first week (o) or against the PSB-CB27-treated group in first week (+) were performed by one-way ANOVA Tukey post hoc. Significant differences are denoted by *,^,o p < 0.05; **,^^ p < 0.01; ***,^^^,###,+++ p < 0.001.

Figure 2

Effect of diet or long-term administration of the GPR18 ligands or rimonabant, on weights of various organs of female Wistar rats in the model of excessive eating. (A) Peritoneal adipose tissue. (B) Heart. (C) Kidneys. (D) Liver. Results are the means ± SEM, n = 6. Multiple comparisons against the vehicle-treated control group (*) or against the vehicle-treated obese control group (^) were performed by one-way ANOVA Tukey post hoc; Significant differences are denoted by *,^ p < 0.05; ***,^^^ p < 0.001.

Figure 3

Effect of long-term administration of the GPR18 ligands or rimonabant, on food (A) or water intake (B) of female Wistar rats fed a palatable feed. Results are the means ± SEM, n = 6. Multiple comparisons against the vehicle-treated control group (*) or against the vehicle-treated obese control group (^) were performed by one-way ANOVA Tukey post hoc; Significant differences are denoted by **,^^ p < 0.01; ***,^^^ p < 0.001.

Figure 4

Effect of administration of the GPR18 ligands or rimonabant on plasma glucose (A), insulin (B), triglyceride (C), total cholesterol (D) or HDL-cholesterol (E) level or alanine aminotransferase (F), aspartate aminotransferase (G), γ-glutamyl transpeptidase, and (H) activity of female Wistar rats fed a palatable feed. Results are the means ± SEM, n = 6. Multiple comparisons against the vehicle-treated control group (*) or against the vehicle-treated obese control group (^) were performed by one-way ANOVA Tukey post hoc; Significant differences are denoted by *,^ p < 0.05, **,^^ p < 0.01, ***,^^^ p < 0.001.

Figure 5

Influence of the GPR18 ligands or rimonabant on locomotor activity after a single dose (A,C,E,G) and chronic treatment (B,D,F,H). Locomotor activity of rats fed palatable feed during 18 h period after treatment with tested compounds (5 mg/kg b.w., i.p.), rimonabant (1 mg/kg b.w.), or vehicle. Activity is directly related to entrance to various areas of the cage. Results are the means ± SEM, n = 6 (multiple t-test). Significant differences are denoted by ^ p < 0.05.

Figure 6

Effect of single administration of the GPR18 ligands or rimonabant, on body weight (A), kaolin intake (B), food intake (C), water intake (D), the amount of feces (E) of female Wistar rats in the Pica behavior model. The effect of multiple (seven days) administration of the GPR18 ligands or rimonabant, on body weight (F), sucrose intake (G), and fluid intake (H) of female Wistar rats in conditioned tested aversion model. Results are the means ± SEM, data for two animals are reared together, n = 6. Multiple comparisons against the vehicle-treated control group (*) or against the vehicle-treated obese control group (^) were performed by one-way ANOVA Tukey post hoc. Significant differences are denoted by *,^ p < 0.05; ^ p < 0.01; ***,^^^ p < 0.001.

Figure 7

A schematic diagram of chronic administration of tested compounds in model of excessive eating. PSB-KK1415 or PSB-CB27 or PSB-CB5 (5 mg/kg b.w.) or rimonabant (1 mg/kg b.w.) were administrated intraperitoneally (i.p.) to rats for 22 consecutive days. Control groups received 1% Tween 80 (A). A schematic diagram of pica behavior test. Rats were treated with single dose of tested compounds (5 mg/kg b.w., i.p.) or rimonabant (1 mg/kg b.w., i.p.). Control group received 1% Tween 80 or CuSO4 (6 mg/kg b.w., i.p.) (B). A schematic diagram of conditioned tasted aversion test. Rats were treated with repeated (seven-times) dose of tested compounds (5 mg/kg b.w., i.p.) or rimonabant (1 mg/kg b.w., i.p.). Control group received 1% Tween 80 or LiCl (40 mg/kg b.w., i.p.). The measurement period began on the seventh day of administration and lasted for the next 24 h (C).