Publications by authors named "Fabio Takeo Sato"

10 Publications

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Small intestine remodeling in male Goto-Kakizaki rats.

Physiol Rep 2021 02;9(3):e14755

Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil.

Background: Obesity is associated with the development of insulin resistance (IR) and type-2 diabetes mellitus (T2DM); however, not all patients with T2DM are obese. The Goto-Kakizaki (GK) rat is an experimental model of spontaneous and non-obese T2DM. There is evidence that the intestine contributes to IR development in GK animals. This information prompted us to investigate small intestine remodeling in this animal model.

Methods: Four-month-old male Wistar (control) and GK rats were utilized for the present study. After removing the small intestine, the duodenum, proximal jejunum, and distal ileum were separated. We then measured villi and muscular and mucosa layer histomorphometry, goblet cells abundance, total myenteric and submucosal neuron populations, and inflammatory marker expression in the small intestinal segments and intestinal transit of both groups of animals.

Key Results: We found that the GK rats exhibited decreased intestinal area (p < 0.0001), decreased crypt depth in the duodenum (p = 0.01) and ileum (p < 0.0001), increased crypt depth in the jejunum (p < 0.0001), longer villi in the jejunum and ileum (p < 0.0001), thicker villi in the duodenum (p < 0.01) and ileum (p < 0.0001), thicker muscular layers in the duodenum, jejunum, and ileum (p < 0.0001), increased IL-1β concentrations in the duodenum and jejunum (p < 0.05), and increased concentrations of NF-κB p65 in the duodenum (p < 0.01), jejunum and ileum (p < 0.05). We observed high IL-1β reactivity in the muscle layer, myenteric neurons, and glial cells of the experimental group. GK rats also exhibited a significant reduction in submucosal neuron density in the jejunum and ileum, ganglionic hypertrophy in all intestinal segments studied (p < 0.0001), and a slower intestinal transit (about 25%) compared to controls.

Conclusions: The development of IR and T2DM in GK rats is associated with small intestine remodeling that includes marked alterations in small intestine morphology, local inflammation, and reduced intestinal transit.
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http://dx.doi.org/10.14814/phy2.14755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881800PMC
February 2021

Tributyrin Attenuates Metabolic and Inflammatory Changes Associated with Obesity through a GPR109A-Dependent Mechanism.

Cells 2020 09 1;9(9). Epub 2020 Sep 1.

Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas 13083007, Brazil.

Obesity is linked with altered microbial short-chain fatty acids (SCFAs), which are a signature of gut dysbiosis and inflammation. In the present study, we investigated whether tributyrin, a prodrug of the SCFA butyrate, could improve metabolic and inflammatory profiles in diet-induced obese mice. Mice fed a high-fat diet for eight weeks were treated with tributyrin or placebo for another six weeks. We show that obese mice treated with tributyrin had lower body weight gain and an improved insulin responsiveness and glucose metabolism, partly via reduced hepatic triglycerides content. Additionally, tributyrin induced an anti-inflammatory state in the adipose tissue by reduction of and and increased , Tregs cells and M2-macrophages. Moreover, improvement in glucose metabolism and reduction of fat inflammatory states associated with tributyrin treatment were dependent on GPR109A activation. Our results indicate that exogenous targeting of SCFA butyrate attenuates metabolic and inflammatory dysfunction, highlighting a potentially novel approach to tackle obesity.
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http://dx.doi.org/10.3390/cells9092007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563536PMC
September 2020

Long-term increase of insulin secretion in mice subjected to pregnancy and lactation.

Endocr Connect 2020 Apr;9(4):299-308

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.

Purpose: Observational studies show that longer breastfeeding periods reduce maternal risk of type 2 diabetes mellitus. However, it is currently unknown if the long-term benefits of breastfeeding for maternal glucose homeostasis are linked to changes in the endocrine pancreas.

Methods: We presently evaluated functional, morphological and molecular aspects of the endocrine pancreas of mice subjected to two sequential cycles of pregnancy and lactation (L21). Age-matched mice not allowed to breastfeed (L0) and virgin mice were used as controls.

Results: L21 mice exhibited increased tolerance and increased glucose-stimulated insulin secretion (GSIS) by isolated islets. Pancreatic islets of L21 mice did not present evident morphological changes to justify the increased GSIS. On the other hand, islets of L21 mice exhibited a reduction in Cavb3 and Kir6.2 expression with concordant increased intracellular Ca2+ levels after challenge with glucose.

Conclusion: Altogether, the present findings show the breastfeeding exerts long-term benefits for maternal endocrine pancreas by increasing intracellular Ca2+ levels and GSIS.
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http://dx.doi.org/10.1530/EC-20-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159261PMC
April 2020

Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2.

J Exp Med 2020 03;217(3)

Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.

Antibiotic-induced dysbiosis is a key predisposing factor for Clostridium difficile infections (CDIs), which cause intestinal disease ranging from mild diarrhea to pseudomembranous colitis. Here, we examined the impact of a microbiota-derived metabolite, short-chain fatty acid acetate, on an acute mouse model of CDI. We found that administration of acetate is remarkably beneficial in ameliorating disease. Mechanistically, we show that acetate enhances innate immune responses by acting on both neutrophils and ILC3s through its cognate receptor free fatty acid receptor 2 (FFAR2). In neutrophils, acetate-FFAR2 signaling accelerates their recruitment to the inflammatory sites, facilitates inflammasome activation, and promotes the release of IL-1β; in ILC3s, acetate-FFAR2 augments expression of the IL-1 receptor, which boosts IL-22 secretion in response to IL-1β. We conclude that microbiota-derived acetate promotes host innate responses to C. difficile through coordinate action on neutrophils and ILC3s.
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http://dx.doi.org/10.1084/jem.20190489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062529PMC
March 2020

New insights on the regulation of cancer cachexia by N-3 polyunsaturated fatty acids.

Pharmacol Ther 2019 04 4;196:117-134. Epub 2018 Dec 4.

Institute of Physical Activity Sciences and Sports, Cruzeiro do Sul University, Sao Paulo, Brazil; Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address:

Cancer cachexia is a multifactorial syndrome that develops during malignant tumor growth. Changes in plasma levels of several hormones and inflammatory factors result in an intense catabolic state, decreased activity of anabolic pathways, anorexia, and marked weight loss, leading to cachexia development and/or accentuation. Inflammatory mediators appear to be related to the control of a highly regulated process of muscle protein degradation that accelerates the process of cachexia. Several mediators have been postulated to participate in this process, including TNF-α, myostatin, and activated protein degradation pathways. Some interventional therapies have been proposed, including nutritional (dietary, omega-3 fatty acid supplementation), hormonal (insulin), pharmacological (clenbuterol), and nonpharmacological (physical exercise) therapies. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid, are recognized for their anti-inflammatory properties and have been used in therapeutic approaches to treat or attenuate cancer cachexia. In this review, we discuss recent findings on cellular and molecular mechanisms involved in inflammation in the cancer cachexia syndrome and the effectiveness of n-3 PUFAs to attenuate or prevent cancer cachexia.
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http://dx.doi.org/10.1016/j.pharmthera.2018.12.001DOI Listing
April 2019

Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases.

Nat Commun 2018 01 9;9(1):105. Epub 2018 Jan 9.

Nuclear Dynamics, Babraham Institute, Cambridge, CB22 3AT, UK.

The recently discovered histone post-translational modification crotonylation connects cellular metabolism to gene regulation. Its regulation and tissue-specific functions are poorly understood. We characterize histone crotonylation in intestinal epithelia and find that histone H3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestine crypt and colon, and is linked to gene regulation. We show that this modification is highly dynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1, HDAC2, and HDAC3, as major executors of histone decrotonylation. We show that known HDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation. Consistent with this, we find that depletion of the gut microbiota leads to a global change in histone crotonylation in the colon. Our results suggest that histone crotonylation connects chromatin to the gut microbiota, at least in part, via short-chain fatty acids and HDACs.
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http://dx.doi.org/10.1038/s41467-017-02651-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760624PMC
January 2018

Marathon Race Affects Neutrophil Surface Molecules: Role of Inflammatory Mediators.

PLoS One 2016 2;11(12):e0166687. Epub 2016 Dec 2.

Institute of Physical Activity and Sports Sciences, University of Cruzeiro do Sul, São Paulo, São Paulo, Brazil.

The fatigue induced by marathon races was observed in terms of inflammatory and immunological outcomes. Neutrophil survival and activation are essential for inflammation resolution and contributes directly to the pathogenesis of many infectious and inflammatory conditions. The aim of this study was to investigate the effect of marathon races on surface molecules related to neutrophil adhesion and extrinsic apoptosis pathway and its association with inflammatory markers. We evaluated 23 trained male runners at the São Paulo International Marathon 2013. The following components were measured: hematological and inflammatory mediators, muscle damage markers, and neutrophil function. The marathon race induced an increased leukocyte and neutrophil counts; creatine kinase (CK), lactate dehydrogenase (LDH), CK-MB, interleukin (IL)-6, IL-10, and IL-8 levels. C-reactive protein (CRP), IL-12, and tumor necrosis factor (TNF)-α plasma concentrations were significantly higher 24 h and 72 h after the marathon race. Hemoglobin and hematocrit levels decreased 72 h after the marathon race. We also observed an increased intercellular adhesion molecule-1 (ICAM-1) expression and decreasedTNF receptor-1 (TNFR1) expression immediately after and 24 h after the marathon race. We observed an increased DNA fragmentation and L-selectin and Fas receptor expressions in the recovery period, indicating a possible slow rolling phase and delayed neutrophil activation and apoptosis. Marathon racing affects neutrophils adhesion and survival in the course of inflammation, supporting the "open-window" post-exercise hypothesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166687PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135050PMC
June 2017

Regulation of immune cell function by short-chain fatty acids.

Clin Transl Immunology 2016 Apr 22;5(4):e73. Epub 2016 Apr 22.

Department of Genetics, Evolution and Bioagents, Institute of Biology, State University of Campinas , Campinas, São Paulo, Brazil.

Short-chain fatty acids (SCFAs) are bacterial fermentation products, which are chemically composed by a carboxylic acid moiety and a small hydrocarbon chain. Among them, acetic, propionic and butyric acids are the most studied, presenting, respectively, two, three and four carbons in their chemical structure. These metabolites are found in high concentrations in the intestinal tract, from where they are uptaken by intestinal epithelial cells (IECs). The SCFAs are partially used as a source of ATP by these cells. In addition, these molecules act as a link between the microbiota and the immune system by modulating different aspects of IECs and leukocytes development, survival and function through activation of G protein coupled receptors (FFAR2, FFAR3, GPR109a and Olfr78) and by modulation of the activity of enzymes and transcription factors including the histone acetyltransferase and deacetylase and the hypoxia-inducible factor. Considering that, it is not a surprise, the fact that these molecules and/or their targets are suggested to have an important role in the maintenance of intestinal homeostasis and that changes in components of this system are associated with pathological conditions including inflammatory bowel disease, obesity and others. The aim of this review is to present a clear and updated description of the effects of the SCFAs derived from bacteria on host immune system, as well as the molecular mechanisms involved on them.
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http://dx.doi.org/10.1038/cti.2016.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855267PMC
April 2016

Fatty acids as modulators of neutrophil recruitment, function and survival.

Eur J Pharmacol 2016 Aug 15;785:50-58. Epub 2015 May 15.

Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas, Rua Monteiro Lobato, 255 Caixa Postal 6109, CEP 13083-862, Campinas/SP, Brazil. Electronic address:

Neutrophils are well-known to act in the destruction of invading microorganisms. They have also been implicated in the activation of other immune cells including B- and T-lymphocytes and in the resolution of inflammation and tissue regeneration. Neutrophils are produced in the bone marrow and released into the circulation from where they migrate to tissues to perform their effector functions. Neutrophils are in constant contact with fatty acids that can modulate their function, activation and fate (survival or cell death) through different mechanisms. In this review, the effects of fatty acids pertaining to five classes, namely, long-chain saturated fatty acids (LCSFAs), short-chain fatty acids (SCFAs), and omega-3 (n-3), omega-6 (n-6) and omega-9 (n-9) unsaturated fatty acids, on neutrophils and the relevance of these effects for disease development are discussed.
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http://dx.doi.org/10.1016/j.ejphar.2015.03.098DOI Listing
August 2016

Effect of regular circus physical exercises on lymphocytes in overweight children.

PLoS One 2015 31;10(3):e0120262. Epub 2015 Mar 31.

Institute of Physical Activity Sciences and Sports, Post-Graduate Program in Human Movement Sciences, Cruzeiro do Sul University, São Paulo, Brazil.

Obesity associated with a sedentary lifestyle can lead to changes in the immune system balance resulting in the development of inflammatory diseases. The aim of this study was to compare lymphocyte activation mechanisms between overweight children practicing regular circus physical exercises with non-exercised children. The study comprised 60 pubescent children randomly divided into 4 groups: Overweight Children (OWC) (10.67 ± 0.22 years old), Overweight Exercised Children (OWE) (10.00 ± 0.41 years old), Eutrophic Children (EC) (11.00 ± 0.29 years old) and Eutrophic Exercised Children (EE) (10.60 ± 0.29 years old). OWE and EE groups practiced circus activities twice a week, for 4.3 ± 0.5 and 4.4 ± 0.5 months, respectively. Percentage of T regulatory cells (Treg) and the expression of CD95 and CD25 in CD4+ lymphocytes were evaluated by flow cytometry. Lymphocyte proliferation capacity was measured by [14C]-thymidine incorporation and mRNA expression of IL-35, TGF-beta, IL-2 and IL-10 by real-time PCR. Lymphocyte proliferation was higher in OWC and OWE groups compared with the EC (3509 ± 887; 2694 ± 560, and 1768 ± 208 cpm, respectively) and EE (2313 ± 111 cpm) groups. CD95 expression on lymphocytes was augmented in the EC (953.9 ± 101.2) and EE groups (736.7 ± 194.6) compared with the OWC (522.1 ± 125.2) and OWE groups (551.6 ± 144.5). CTLA-4 expression was also lower in the OWC and OWE groups compared with the EC and EE groups. Percentage of Treg, IL-35, and IL-10 mRNA expression were lower in the OWC and OWE groups compared with the EC and EE groups. In conclusion, overweight children present altered immune system balance characterized by elevated lymphocyte proliferation due to a decrease in T regulatory cell percentage. These effects were partially reverted by moderate physical exercise, as demonstrated by decreased lymphocyte proliferation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120262PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380297PMC
March 2016
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