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

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.

Evaluation of Anti Anorectic Activity of Zingiber officinale R. (Zingiberaceae)

A rhizome of Zingiber officinale R. commonly known as Ginger is one of the most popular anti-inflammatory drug in Indian traditional medicine. 6-gingerol is one of the constituent contributing in anti-inflammatory activity of Ginger. Ginger extract and 6-gingerol act as an anti inflammatory via inhibition of proinflammatory cytokines. Increase in proinflammatory cytokines is also responsible for the reduction in food intake resulting anorexia. The aim of the present study was thus to determine antianorectic activity of standardized hydroalcoholic extract of ginger and similarly the biomarker 6- gingerol was also studied to evaluate its contribution in antianorectic activity. Anorexia was induced by intraperitoneal administration of E.coli lipopolysaccharide (100µg/kg) and Fluoxetine (FLU 8mg/kg) in rats. The effect of same doses of the extract was also tested in freely feeding rats. Effect of ginger and 6- gingerol both were studied The results showed that at 200 and 400 mg/kg, ginger reversed the anorectic effect while 6- gingerol at 5mg/ kg require for the effect. Moreover the same doses did not modify the food intake in freely feeding rats. These findings provide strong evidence that ginger is ableto attenuate anorexia induced by proinflammatory cytokines mediators.

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus–pituitary–adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.