Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice
Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice
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DOI：
10.1016/j.cmet.2006.04.004
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发表时间：
2006-05-01
期刊：
影响因子：
29
通讯作者：
Smith, Roy G.
中科院分区：
文献类型：
--
作者：
Sun, Yuxiang;Asnicar, Mark;Smith, Roy G.
Ghrelin和瘦素被认为是调节摄食行为的下丘脑神经元上的相互拮抗剂，调节能量稳态。我们采用反向遗传学研究ghrelin和瘦素之间的相互作用。瘦素缺陷小鼠（ob/ob）是贪食、肥胖和高血糖的。出乎意料的是，在ob/ob小鼠中消除生长素释放肽未能挽救肥胖的超噬表型，表明ob/ob表型不是生长素释放肽不受瘦素对抗的结果。值得注意的是，生长素释放肽的缺失增加了胰岛素分泌，以响应葡萄糖的挑战，并增加外周胰岛素敏感性;事实上，当ob/ob小鼠繁殖到生长素释放肽（-/-）的背景下时，ob/ob小鼠表现出的高血糖症显着减少。我们进一步证明，消融生长激素释放肽减少胰腺中Ucp 2 mRNA的表达，这有助于增强葡萄糖诱导的胰岛素分泌。因此，长期而言，ghrelin通过调节胰腺Ucp 2表达和胰岛素敏感性来控制葡萄糖稳态。
Ghrelin and leptin are suggested to regulate energy homeostasis as mutual antagonists on hypothalamic neurons that regulate feeding behavior. We employed reverse genetics to investigate the interplay between ghrelin and leptin. Leptin-deficient mice (ob/ob) are hyperphagic, obese, and hyperglycemic. Unexpectedly, ablation of ghrelin in ob/ob mice fails to rescue the obese hyperphagic phenotype, indicating that the ob/ob phenotype is not a consequence of ghrelin unopposed by leptin. Remarkably, deletion of ghrelin augments insulin secretion in response to glucose challenge and increases peripheral insulin sensitivity; indeed, the hyperglycemia exhibited by ob/ob mice is markedly reduced when ob/ob mice are bred onto the ghrelin(-/-) background. We further demonstrate that ablation of ghrelin reduces expression of Ucp2 mRNA in the pancreas, which contributes toward enhanced glucose-induced insulin secretion. Hence, chronically, ghrelin controls glucose homeostasis by regulating pancreatic Ucp2 expression and insulin sensitivity.