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Reduced Intestinal Absorption of Dipeptides via PepT1 in Mice with Diet-induced Obesity Is Associated with Leptin Receptor Down-regulation*

机译:降低PepT1在小鼠体内对二肽的肠道吸收 饮食引起的肥胖与瘦素受体有关。 下调*

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摘要

Leptin is a major determinant of energy homeostasis, acting both centrally and in the gastrointestinal tract. We previously reported that acute leptin treatment enhances the absorption of di- and tripeptides via the proton-dependent PepT1 transporter. In this study, we investigated the long term effect of leptin on PepT1 levels and activity in Caco2 cell monolayers in vitro. We then assessed the significance of the regulation of PepT1 in vivo in a model of diet-induced obesity. We demonstrated that 1) leptin regulated PepT1 at the transcriptional level, via the MAPK pathway, and at the translational level, via ribosomal protein S6 activation, in Caco2 cells and 2) this activation was systematically followed by a time- and concentration-dependent loss of leptin action reflecting desensitization. Deciphering this desensitization, we demonstrated that leptin induced a down-regulation of its own receptor protein and mRNA expression. More importantly, we showed, in mice with diet-induced obesity, that a 4-week hypercaloric diet resulted in a 46% decrease in PepT1-specific transport, because of a 30% decrease in PepT1 protein and a 50% decrease in PepT1 mRNA levels. As shown in Caco2 cells, these changes in PepT1 were supported by a parallel 2-fold decrease in leptin receptor expression in mice. Taken together, these results indicate that during induction of obesity, leptin resistance may also occur peripherally in the gastrointestinal tract, disrupting the absorption of oligopeptides and peptidomimetic drugs.
机译:瘦素是能量稳态的主要决定因素,它在中枢和胃肠道中均起作用。我们先前曾报道急性瘦素治疗通过质子依赖的PepT1转运蛋白增强二肽和三肽的吸收。在这项研究中,我们调查了瘦素对PepT1水平和Caco2细胞单层细胞体外活性的长期影响。然后,我们在饮食诱导的肥胖模型中评估了体内PepT1调控的重要性。我们证明了1)瘦素在转录水平上通过MAPK途径调节PepT1,在翻译水平上通过核糖体蛋白S6激活调节Caco2细胞中的PepT1; 2)该激活被系统地跟随时间和浓度依赖性损失瘦素作用反映脱敏。解密这种脱敏,我们证明瘦素诱导其自身受体蛋白和mRNA表达的下调。更重要的是,我们发现,在饮食诱发肥胖的小鼠中,高热量饮食4周导致PepT1特异性转运减少46%,因为PepT1蛋白减少30%和PepT1 mRNA减少50%水平。如在Caco2细胞中所示,小鼠瘦素受体表达的平行2倍下降支持了PepT1的这些变化。综上所述,这些结果表明在肥胖诱导期间,瘦素抗性也可能在胃肠道的周围发生,从而破坏了寡肽和拟肽药物的吸收。

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