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.

Histamine H3 Receptor Ligands—KSK-59 and KSK-73—Reduce Body Weight Gain in a Rat Model of Excessive Eating

“…In the presented model, experimental animals had continuous access to standard diet, which was additionally enriched with high-calorie products such as cheese, peanuts, chocolate or condensed milk. Such a model allows not only for the development of obesity and increase in the amount of fat in the peritoneum in the studied animals, but also for the development of certain metabolic disorders [11,12,18,19]. Already after the first week of the experiment, we noticed that animals from the control group that consumed palatable feed weighed significantly more than animals that consumed only standard feed.…”

“…The experience related to this model suggests that greater differences in body weight changes and in selected metabolic parameters are observed in female rats [12,18,19,46]. Therefore, in preliminary studies, to make the effect more noticeable and in line with the principle of reducing the number of animals (with greater differences fewer animals per experimental group can be used to demonstrate statistical significance), female rats were selected.…”

“…was administrated i.p. [18,19]. Blood samples were taken at the time points: 0 (before glucose administration), 30, 60 and 120 min after administration from the tail vein [11].…”

The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects

“…A growing number of studies investigating the endocannabinoid system has highlighted its involvement in various physiological or pathological processes. This evidence may offer valuable insights, eventually leading to the development of therapeutic drugs for a variety of conditions ranging from mood disorders, obesity, metabolic syndrome, as well as neurodegenerative and cardiovascular diseases [ 1 , 2 , 3 , 4 ].…”

“…Moreover, these compounds displayed higher potency and efficacy than THC [ 11 ]. In addition, PSB-KK-1415 has recently been developed as a novel potent and selective cannabinoid receptors with increased potency agonist [ 4 , 14 ]. Derivatives of imidazothiazinones, namely PSB-CB5, PSB-CB27, and PSB-CB-92 are the most potent synthetic GPR18 antagonists developed to date [ 12 , 15 ].…”