Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino M A, Kasuga M
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.
Gut. 2003 Jul;52(7):947-52. doi: 10.1136/gut.52.7.947.
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.
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.
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.
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.
胃饥饿素是生长激素促分泌素受体（GHS-R）的内源性配体，是一种来自胃的食欲刺激信号，其结构与胃动素相似。我们研究了胃肽胃饥饿素和GHS-R拮抗剂对小鼠能量平衡和血糖控制的影响。
在高脂饮食下重复给予胃饥饿素后，测量体重、脂肪量、血糖、胰岛素以及白色脂肪组织（WAT）中瘦素、脂联素和抵抗素的基因表达。通过Northern印迹分析评估胃饥饿素基因的表达。给予GHS-R拮抗剂后测量能量摄入和胃排空情况。在ob/ob肥胖小鼠中持续六天重复给予GHS-R拮抗剂。
在高脂饮食下，胃饥饿素可导致显著肥胖并使血糖控制恶化。配对喂养可抑制这种效应。胃饥饿素可提高瘦素mRNA表达并降低抵抗素mRNA表达。高脂饮食可增加禁食期间胃饥饿素mRNA的表达。GHS-R拮抗剂可降低瘦小鼠、饮食诱导肥胖小鼠和ob/ob肥胖小鼠的能量摄入；还可降低胃排空率。在ob/ob肥胖小鼠中重复给予GHS-R拮抗剂可减少体重增加并改善血糖控制。
胃饥饿素似乎与体重过度增加、肥胖和胰岛素抵抗密切相关，尤其是在高脂饮食和动态阶段。胃肽胃饥饿素和GHS-R不仅可能是治疗厌食-恶病质的有前景的治疗靶点，也是治疗肥胖和2型糖尿病的有前景的治疗靶点，这两种疾病在全球范围内正日益普遍。
