Disruption of leptin receptor expression in the pancreas directly affects β cell growth and function in mice
Disruption of leptin receptor expression in the pancreas directly affects β cell growth and function in mice
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DOI：
10.1172/jci30910
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发表时间：
2007-10-01
影响因子：
15.9
通讯作者：
Kulkarni, Rohit N.
中科院分区：
文献类型：
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作者：
Morioka, Tomoaki;Asilmaz, Esra;Kulkarni, Rohit N.
肥胖的特征是高胰岛素血症、高瘦素血症和胰岛体积增加。虽然肥胖者加速糖尿病发病的机制尚不清楚，但脂肪源性激素瘦素可能发挥了作用。除了其中枢作用外，瘦素还通过作用于包括内分泌胰腺在内的外周组织来发挥生物效应。为了探索破坏胰腺中瘦素信号传导对 β 细胞生长和/或功能的影响，我们使用在胰腺和十二指肠同源盒 1 (Pdx1) 启动子控制下表达 Cre 重组酶的小鼠创建了胰腺特异性瘦素受体 (ObR) KO。 KOs 由于早期胰岛素分泌增强而表现出改善的葡萄糖耐量，并且由于β细胞大小增加以及p70S6K表达和磷酸化增强而继发了更大的β细胞质量。在敲低 ObR 基因的 MIN6 β 细胞中观察到对 p70S6K 的类似影响，表明瘦素和胰岛素信号通路之间存在串扰。令人惊讶的是，用高脂肪饮食挑战 KO 会导致对葡萄糖的急性胰岛素分泌反应减弱、代偿性胰岛生长不良和葡萄糖不耐受。总之，这些数据从仅在胰腺中缺乏 ObR 的独特小鼠模型中提供了直接的遗传证据，表明瘦素信号在胰岛生物学中发挥着关键作用，并表明胰岛中瘦素作用的改变是导致肥胖相关糖尿病的一个因素。
Obesity is characterized by hyperinsulinemia, hyperleptinemia, and an increase in islet volume. While the mechanisms that hasten the onset of diabetes in obese individuals are not known, it is possible that the adipose-derived hormone leptin plays a role. In addition to its central actions, leptin exerts biological effects by acting in peripheral tissues including the endocrine pancreas. To explore the impact of disrupting leptin signaling in the pancreas on beta cell growth and/or function, we created pancreas-specific leptin receptor (ObR) KOs using mice expressing Cre recombinase under the control of the pancreatic and duodenal homeobox 1 (Pdx1) promoter. The KOs exhibited improved glucose tolerance due to enhanced early-phase insulin secretion, and a greater beta cell mass secondary to increased beta cell size and enhanced expression and phosphorylation of p70S6K. Similar effects on p70S6K were observed in MIN6 beta cells with knockdown of the ObR gene, suggesting crosstalk between leptin and insulin signaling pathways. Surprisingly, challenging the KOs with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Together, these data provide direct genetic evidence, from a unique mouse model lacking ObRs only in the pancreas, for a critical role for leptin signaling in islet biology and suggest that altered leptin action in islets is one factor that contributes to obesity-associated diabetes.