High-Fat Diet Induces Disruption of the Tight Junction-Mediated Paracellular Barrier in the Proximal Small Intestine Bef
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ORIGINAL ARTICLE
High‑Fat Diet Induces Disruption of the Tight Junction‑Mediated Paracellular Barrier in the Proximal Small Intestine Before the Onset of Type 2 Diabetes and Endotoxemia J. C. Nascimento1 · V. A. Matheus1 · R. B. Oliveira1 · S. F. S. Tada1 · Carla B. Collares‑Buzato1 Received: 4 February 2020 / Accepted: 6 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Background/Aim A link between an impaired intestinal barrier, endotoxemia, and the pathogenesis of metabolic diseases, such as type 2 diabetes mellitus (T2DM), has been proposed. In previous work, we have demonstrated that the tight junction (TJ)-mediated intestinal barrier in ileum/colon was marginally changed in prediabetic mice; therefore, it does not seem to mainly contribute to the T2DM onset. In this study, the TJ-mediated epithelial barrier in the duodenum and jejunum was evaluated in mice during the development of type 2 prediabetes. Methods/Results HF diet induced prediabetes after 60 days associated with a significant rise in intestinal permeability to the small-sized marker Lucifer yellow in these mice, with no histological signs of mucosal inflammation or rupture of the proximal intestine epithelium. As revealed by immunofluorescence, TJ proteins, such as claudins-1, -2, -3, and ZO-1, showed a significant decrease in junctional content in duodenum and jejunum epithelia, already after 15 days of treatment, suggesting a rearrangement of the TJ structure. However, no significant change in total cell content of these proteins was observed in intestinal epithelium homogenates, as assessed by immunoblotting. Despite the changes in intestinal permeability and TJ structure, the prediabetic mice showed similar LPS, zonulin, and TNF-α levels in plasma or adipose tissue, and in intestinal segments as compared to the controls. Conclusion Disruption of the TJ-mediated paracellular barrier in the duodenum and jejunum is an early event in prediabetes development, which occurs in the absence of detectable endotoxemia/inflammation and may contribute to the HF diet-induced increase in intestinal permeability. Keywords Type 2 prediabetes · Claudins · Intestinal barrier · Obesity
Introduction Type 2 diabetes mellitus (T2DM) is an endocrine-metabolic disease with complex pathogenesis, whose etiology is not yet fully elucidated. Recent studies have proposed that prolonged exposure to a high-fat (HF) diet leads to the development of T2DM by mechanisms involving changes in the Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10620-020-06664-x) contains supplementary material, which is available to authorized users. * Carla B. Collares‑Buzato [email protected] 1
Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP CEP 13083‑970, Brazil
intestinal microbiota, increase in the proportion of Gramnegative bacteria associated with intestinal barrier impairment, favoring the chronic absorption of lipop
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