STOMACH

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

A Asakawa¹, A Inui¹, T Kaga¹, G Katsuura², M Fujimiya³, M A Fujino⁴, M Kasuga¹

¹ Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
² Shionogi Research Laboratories, Shionogi and Co Ltd, Shiga 520-3423, Japan
³ Department of Anatomy, Shiga University of Medical Science, Shiga 520-2192, Japan
⁴ First Department of Internal Medicine, Yamanashi Medical University, Yamanashi 409-3898, Japan

Correspondence to:
Correspondence to:
Dr A Inui, Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650–0017, Japan;
inui{at}med.kobe-u.ac.jp

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.

Keywords: ghrelin; growth hormone secretagogue receptor; obesity; diabetes; stomach

Abbreviations: AGRP, agouti related protein; ARC, arcuate nucleus; FFA, free fatty acids; GH, growth hormone; GHRP, growth hormone releasing peptide; GHS-R, growth hormone secretagogue receptor; ICV, intra-third cerebroventricular(ly); NPY, neuropeptide Y; WAT, white adipose tissue

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