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      Wide-range screening of anti-inflammatory compounds in tomato using LC-MS and elucidating the mechanism of their functions

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          Abstract

          Obesity-induced chronic inflammation is a key factor in type 2 diabetes. A vicious cycle involving pro-inflammatory mediators between adipocytes and macrophages is a common cause of chronic inflammation in the adipose tissue. Tomato is one of the most popular vegetables and is associated with a reduced risk of diabetes. However, the molecular mechanism underlying the effect of tomato on diabetes is unclear. In this study, we focused on anti-inflammatory compounds in tomato. We found that the extract of tomato reduced plasma glucose and inflammatory markers in mice. We screened anti-inflammatory fractions in tomato using lipopolysaccharide-stimulated RAW264.7 macrophages, and active compounds were estimated by liquid chromatography-mass spectrometry over a wide range. Surprisingly, a large number of compounds including oxylipin and coumarin derivatives were estimated as anti-inflammatory compounds. Especially, 9-oxo-octadecadienoic acid and daphnetin suppressed pro-inflammatory cytokines in RAW264.7 macrophages inhibiting mitogen-activated protein kinase phosphorylation and inhibitor of kappa B α protein degradation. These findings suggest that tomato containing diverse anti-inflammatory compounds ameliorates chronic inflammation in obese adipose tissue.

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          Most cited references37

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          MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.

          Adipocytes secrete a variety of bioactive molecules that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1 (MCP-1) mRNA in adipose tissue and the plasma concentration of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-negative mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.
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            Insulin sensitivity: modulation by nutrients and inflammation.

            Insulin resistance is a major metabolic feature of obesity and is a key factor in the etiology of a number of diseases, including type 2 diabetes. In this review, we discuss potential mechanisms by which brief nutrient excess and obesity lead to insulin resistance and propose that these mechanisms of action are different but interrelated. We discuss how pathways that "sense" nutrients within skeletal muscle are readily able to regulate insulin action. We then discuss how obesity leads to insulin resistance via a complex interplay among systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation. In particular, we focus on the hypothesis that the macrophage is an important cell type in the propagation of inflammation and induction of insulin resistance in obesity. Overall, we provide our integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity.
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              Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis.

              Metabolism and immunity are inextricably linked both to each other and to organism-wide function, allowing mammals to adapt to changes in their internal and external environments. In the modern context of obesogenic diets and lifestyles, however, these adaptive responses can have deleterious consequences. In this Review, we discuss the pleiotropic actions of inflammation and insulin resistance in metabolic homeostasis and disease. An appreciation of the adaptive context in which these responses arose is useful for understanding their pathogenic actions in disease.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Methodology
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Investigation
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 January 2018
                2018
                : 13
                : 1
                : e0191203
                Affiliations
                [1 ] Laboratory of Molecular Function of Food, Graduate School of Agriculture, Kyoto University, Uji, Kyoto, Japan
                [2 ] KAGOME Tomato Discoveries Laboratory, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
                [3 ] Innovation Division, KAGOME CO., LTD., Tochigi, Japan
                [4 ] Laboratory of Quality Analysis and Assessment, Graduate School of Agriculture, Kyoto University, Uji, Kyoto, Japan
                [5 ] Kazusa DNA Research Institutes, Kazusa-Kamatari, Kisarazu, Chiba, Japan
                [6 ] Research Unit for Physiological Chemistry, Kyoto University, Kyoto, Japan
                Tokyo University of Agriculture, JAPAN
                Author notes

                Competing Interests: In this study, the authors received funding by KAGOME CO., LTD. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Article
                PONE-D-17-31545
                10.1371/journal.pone.0191203
                5766234
                29329333
                a00d0b83-9693-4906-9a49-36a803df46e1
                © 2018 Mohri et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 28 August 2017
                : 30 December 2017
                Page count
                Figures: 6, Tables: 7, Pages: 21
                Funding
                Funded by: Japan Society for the Promotion of Science (JP)
                Award ID: 16H02551
                Award Recipient :
                Funded by: Japan Society for the Promotion of Science (JP)
                Award ID: 16K14927
                Award Recipient :
                Funded by: Japan Society for the Promotion of Science (JP)
                Award ID: 16K07734
                Award Recipient :
                Funded by: Japan Society for the Promotion of Science (JP)
                Award ID: 16K18703
                Award Recipient :
                This study was funded by KAGOME CO., LTD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Eukaryota
                Plants
                Fruits
                Tomatoes
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Research and Analysis Methods
                Chromatographic Techniques
                Liquid Chromatography
                Liquid Chromatography-Mass Spectrometry
                Physical Sciences
                Chemistry
                Analytical Chemistry
                Mass Spectrometry
                Liquid Chromatography-Mass Spectrometry
                Research and Analysis Methods
                Spectrum Analysis Techniques
                Mass Spectrometry
                Liquid Chromatography-Mass Spectrometry
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Inflammation
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
                Research and Analysis Methods
                Chromatographic Techniques
                Liquid Chromatography
                High Performance Liquid Chromatography
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Adipose Tissue
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Adipose Tissue
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Secretion
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Secretion
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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