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


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.
Asakawa
A
A
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
A
A
Kaga
T
T
Katsuura
G
G
Fujimiya
M
M
Fujino
M A
MA
Kasuga
M
M
D052242:Adiponectin; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology; D005746:Gastric Emptying / Q000502:physiology; D015870:Gene Expression; D054439:Ghrelin; D005947:Glucose / Q000032:analysis; D006729:Hormones, Ectopic / Q000032:analysis; D007328:Insulin / Q000032:analysis; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D020932:Nerve Growth Factor; D036361:Peptide Hormones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011506:Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D052243:Resistin; D015430:Weight Gain / Q000502:physiology*
D052242:Adiponectin; D004041:Dietary Fats; D054439:Ghrelin; D006729:Hormones, Ectopic; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D036361:Peptide Hormones; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D052243:Resistin; C499623:Retn protein, mouse; C413576:Retnla protein, mouse; D020932:Nerve Growth Factor; D005947:Glucose