Sun Yuxiang, Asnicar Mark, Saha Pradip K, Chan Lawrence, Smith Roy G
Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cell Metab. 2006 May;3(5):379-86. doi: 10.1016/j.cmet.2006.04.004.
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.
胃饥饿素和瘦素被认为是作为下丘脑调节进食行为的神经元上的相互拮抗剂来调节能量平衡。我们采用反向遗传学来研究胃饥饿素和瘦素之间的相互作用。瘦素缺乏的小鼠（ob/ob）食欲亢进、肥胖且血糖过高。出乎意料的是，在ob/ob小鼠中去除胃饥饿素并不能挽救肥胖、食欲亢进的表型，这表明ob/ob表型不是胃饥饿素未被瘦素对抗的结果。值得注意的是，去除胃饥饿素会增强对葡萄糖刺激的胰岛素分泌并增加外周胰岛素敏感性；实际上，当将ob/ob小鼠培育到胃饥饿素基因敲除（-/-）背景时，ob/ob小鼠所表现出的高血糖症会显著降低。我们进一步证明，去除胃饥饿素会降低胰腺中Ucp2 mRNA的表达，这有助于增强葡萄糖诱导的胰岛素分泌。因此，长期来看，胃饥饿素通过调节胰腺Ucp2表达和胰岛素敏感性来控制葡萄糖稳态。
