Obesity-induces Organ and Tissue Specific Tight Junction Restructuring and Barrier Deregulation by Claudin Switching.
Obesity-induces Organ and Tissue Specific Tight Junction Restructuring and Barrier Deregulation by Claudin Switching.
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DOI：
10.1038/s41598-017-04989-8
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发表时间：
2017-07-11
影响因子：
4.6
通讯作者：
Singh AB
中科院分区：
文献类型：
--
作者：
Ahmad R;Rah B;Bastola D;Dhawan P;Singh AB
肥胖增加了多器官疾病的易感性，然而，潜在的机制仍不清楚。由肥胖诱导的肠道通透性辅助的亚临床炎症可能是肥胖相关共病的基础。尽管肥胖导致的肠道屏障异常具有显著的临床意义，但其精确的分子调控仍不清楚。也不清楚屏障失调是否与肠道相似，是肥胖个体其他重要器官的特征。紧密连接蛋白家族是紧密连接（TJ）、顶端细胞-细胞粘附和上皮屏障的关键调节剂的组成部分。使用对来自高脂肪饮食喂养的小鼠的肠和肾组织的全面生理和生化分析，这对于维持代谢稳态至关重要，本研究表明，通过器官和组织特异性claudin转换的深刻TJ重构表征了肥胖器官。检测蛋白表达和细胞分布。计算机模拟分析进一步强调了由肥胖调节的所选密封蛋白与具有病理学意义的信号传导和代谢途径的潜在关联。使用瘦素或DCA治疗的体外研究表明，肥胖诱导的组织微环境变化在以组织特异性方式调节屏障失调中具有因果意义。总体而言，目前的研究结果推进了我们对肥胖相关变化的分子承诺的理解，这些变化有助于易感特定疾病，并确定了预防和/或治疗干预的新窗口。
Obesity increases susceptibility to multiple organ disorders, however, underlying mechanisms remain unclear. The subclinical inflammation assisted by obesity-induced gut permeability may underlie obesity-associated co-morbidities. Despite eminent clinical significance of the obesity led gut barrier abnormalities, its precise molecular regulation remains unclear. It is also unknown whether barrier deregulations, similar to the gut, characterize other vital organs in obese individuals. The claudin family of proteins is integral to the tight junction (TJ), the apical cell-cell adhesion and a key regulator of the epithelial barrier. Using comprehensive physiological and biochemical analysis of intestinal and renal tissues from high-fat diet fed mice, critical for maintaining metabolic homeostasis, this study demonstrates that profound TJ-restructuring by organ and tissue-specific claudin switching characterize obese organs. Protein expression and cellular distribution were examined. In-silico analysis further highlighted potential association of select claudins, modulated by the obesity, with signaling and metabolic pathways of pathological significance. In vitro studies using Leptin or DCA-treatment suggested causal significance of obesity-induced changes in tissue microenvironment in regulating barrier deregulations in tissue-specific manner. Overall, current findings advances our understanding of the molecular undertakings of obesity associated changes that help predispose to specific diseases and also identifies novel windows of preventive and/or therapeutic interventions.
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影响因子：
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作者：
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