Antagonism of ghrelin receptor reduces food intake and body weight gain in mice

Abstract

Background and aims: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), is an appetite stimulatory signal from the stomach with structural resemblance to motilin. We examined the effects of the gastric peptide ghrelin and GHS-R antagonists on energy balance and glycaemic control in mice. Materials and methods: Body weight, fat mass, glucose, insulin, and gene expression of leptin, adiponectin, and resistin in white adipose tissue (WAT) were measured after repeated administrations of ghrelin under a high fat diet. Gastric ghrelin gene expression was assessed by northern blot analysis. Energy intake and gastric emptying were measured after administration of GHS-R antagonists. Repeated administration of GHS-R antagonist was continued for six days in ob/ob obese mice. Results: Ghrelin induced remarkable adiposity and worsened glycaemic control under a high fat diet. Pair feeding inhibited this effect. Ghrelin elevated leptin mRNA expression and reduced resistin mRNA expression. Gastric ghrelin mRNA expression during fasting was increased by a high fat diet. GHS-R antagonists decreased energy intake in lean mice, in mice with diet induced obesity, and in ob/ob obese mice; it also reduced the rate of gastric emptying. Repeated administration of GHS-R antagonist decreased body weight gain and improved glycaemic control in ob/ob obese mice.Conclusions: Ghrelin appears to be closely related to excess weight gain, adiposity, and insulin resistance, particularly under a high fat diet and in the dynamic stage. Gastric peptide ghrelin and GHS-R may be promising therapeutic targets not only for anorexia-cachexia but also for obesity and type 2 diabetes, which are becoming increasingly prevalent worldwide.

Increase in Ghrelin Levels After Weight Loss in Obese Zucker Rats is Prevented by Gastric Banding

“…Food-restricted rats pair-fed to the gastric banded ones had fasting ghrelin levels significantly higher than obese rats fed ad libitum, a feature that was not observed in gastric banded rats, in spite of similar decrease in food intake and weight loss. Ghrelin is a 28-amino-acid peptide hormone produced mainly in the stomach fundus and is the most potent appetitestimulating hormone coming from the gastrointestinal tract [29]. Ghrelin is generally up-regulated under conditions of negative energy balance and down-regulated in the setting of positive energy balance; fasting serum ghrelin levels are usually low in obese subjects compared with lean individuals [30], and fasting plasma levels rise with diet induced weight loss [14,31].…”

The role of the central ghrelin system in reward from food and chemical drugs

“…The orexigenic and adipogenic effects of ghrelin can be suppressed by ghrelin antagonists (Asakawa et al 2003;Esler et al 2007;Salomé et al 2009a;Salomé et al 2009b). One week peripheral treatment of rats with the GHS-R1A antagonist, JMV2959, suppressed preference for palatable/rewarding food, and they did not gain as much weight as the vehicle-treated control rats .…”

Sequence, genomic organization and expression of ghrelin receptor in grass carp, Ctenopharyngodon idellus

“…Several studies have also examined ghrelin's role in body weight homeostasis and as an important indicator of energy insufficiency (Kamegai et al, 2000;Tschop et al, 2000;Wisse et al, 2001;Wang et al, 2002;Asakawa et al, 2003;Yasuda et al, 2003). The central role of ghrelin in body weight homeostasis and the critical importance of GHS-R in transmitting ghrelin's energy balance and GH secretory messages are highlighted by recent studies on a GHS-R knockout mouse model (Sun et al, 2004(Sun et al, , 2008.…”