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Adipose tissue dysfunction as a central mechanism leading to dysmetabolic obesity triggered by chronic exposure to p,p'-DDE
Publication . Pestana, Diogo; Teixeira, Diana; Meireles, Manuela; Marques, Cláudia S; Norberto, Sónia; Sá, Carla; Fernandes, Virgínia C.; Correia-Sá, Luísa; Faria, Ana S.; Guardão, Luísa; Guimarães, João T.; Cooper, Wendy N.; Sandovici, Ionel; Domingues, Valentina F.; Delerue-Matos, Cristina; Monteiro, Rosário; Constância, Miguel; Calhau, Conceição; Calhau, Conceição; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Nature Publishing Group
Endocrine-disrupting chemicals such as p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), are bioaccumulated in the adipose tissue (AT) and have been implicated in the obesity and diabetes epidemic. Thus, it is hypothesized that p,p'-DDE exposure could aggravate the harm of an obesogenic context. We explored the effects of 12 weeks exposure in male Wistar rats' metabolism and AT biology, assessing a range of metabolic, biochemical and histological parameters. p,p'-DDE -treatment exacerbated several of the metabolic syndrome-accompanying features induced by high-fat diet (HF), such as dyslipidaemia, glucose intolerance and hypertension. A transcriptome analysis comparing mesenteric visceral AT (vAT) of HF and HF/DDE groups revealed a decrease in expression of nervous system and tissue development-related genes, with special relevance for the neuropeptide galanin that also revealed DNA methylation changes at its promoter region. Additionally, we observed an increase in transcription of dipeptidylpeptidase 4, as well as a plasmatic increase of the pro-inflammatory cytokine IL-1β. Our results suggest that p,p'-DDE impairs vAT normal function and effectively decreases the dynamic response to energy surplus. We conclude that p,p'-DDE does not merely accumulate in fat, but may contribute significantly to the development of metabolic dysfunction and inflammation. Our findings reinforce their recognition as metabolism disrupting chemicals, even in non-obesogenic contexts.
Gut microbiota modulation accounts for the neuroprotective properties of anthocyanins
Publication . Marques, C.; Fernandes, I.; Meireles, M.; Faria, A.; Spencer, J.P.E.; Mateus, N.; Calhau, C.; Calhau, Conceição; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Nature Publishing Group
High-fat (HF) diets are thought to disrupt the profile of the gut microbiota in a manner that may contribute to the neuroinflammation and neurobehavioral changes observed in obesity. Accordingly, we hypothesize that by preventing HF-diet induced dysbiosis it is possible to prevent neuroinflammation and the consequent neurological disorders. Anthocyanins are flavonoids found in berries that exhibit anti-neuroinflammatory properties in the context of obesity. Here, we demonstrate that the blackberry anthocyanin-rich extract (BE) can modulate gut microbiota composition and counteract some of the features of HF-diet induced dysbiosis. In addition, we show that the modifications in gut microbial environment are partially linked with the anti-neuroinflammatory properties of BE. Through fecal metabolome analysis, we unravel the mechanism by which BE participates in the bilateral communication between the gut and the brain. BE alters host tryptophan metabolism, increasing the production of the neuroprotective metabolite kynurenic acid. These findings strongly suggest that dietary manipulation of the gut microbiota with anthocyanins can attenuate the neurologic complications of obesity, thus expanding the classification of psychobiotics to anthocyanins. © 2018, The Author(s).
The role of I-FABP as a biomarker of intestinal barrier dysfunction driven by gut microbiota changes in obesity
Publication . Lau, Eva; Marques, Claudia; Pestana, Diogo; Santoalha, Mariana; Carvalho, Davide; Freitas, Paula; Calhau, Conceicao; Calhau, Conceição; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Springer Verlag
Background: Intestinal fatty-acid binding protein (I-FABP) is expressed in epithelial cells of the mucosal layer of the small intestine tissue. When intestinal mucosal damage occurs, I-FABP is released into the circulation and its plasma concentration increases. In the context of obesity, the gut barrier integrity can be disrupted by dietary fat while intestinal permeability increases. Objective: To investigate whether intestinal fatty acid binding protein (I-FABP) is a suitable plasma marker of intestinal injury and inflammation in obesity. Methods: Twelve male Wistar rats were randomly divided into two groups of six animals each: standard (St) and high-fat (HF) diet fed groups for 12 weeks. Results: HF fed animals developed obesity, insulin resistance and seemed to present increased plasma levels of proinflammatory cytokines (MCP-1 and IL1 beta). The gut microbiota composition of these animals was also altered, with lower number of copies of Bacteroidetes, Prevotella spp. and Lactobacillus spp., in comparison with those from St diet group. Fecal lipopolysaccharide (LPS) concentrations tended to be increased in HF fed animals. Intestinal expression of TLR4 seemed to be also increased in HF fed animals suggesting that HF diet-induced dysbiosis may be behind the systemic inflammation observed. However, in contrast to other intestinal inflammatory diseases, plasma I-FABP levels were decreased in HF fed rats whereas I-FABP expression in jejunum tended to be increased. Conclusions: HF diet-induced obesity is characterized by dysbiosis, insulin resistance and systemic inflammation. In this context, plasmatic I-FABP should not be used as a marker of the intestinal barrier dysfunction and the low-grade chronic inflammatory status.
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Fundação para a Ciência e a Tecnologia
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SFRH
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SFRH/BD/93073/2013