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      Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium

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          Abstract

          Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by secretion of interleukin (IL)-1β, IL-6 and IL-8. How metabolic stress impacts tissue responses to pathogens is unclear, but integration of energy metabolism and innate immunity means that stressing one system might affect the other. Here we tested the hypothesis that homeostatic pathways integrate energy metabolism and innate immunity in bovine endometrial tissue. Glucose deprivation reduced the secretion of IL-1β, IL-6 and IL-8 from ex vivo organ cultures of bovine endometrium challenged with the pathogen-associated molecular patterns lipopolysaccharide and bacterial lipopeptide. Endometrial inflammatory responses to lipopolysaccharide were also reduced by small molecules that activate or inhibit the intracellular sensor of energy, AMP-activated protein kinase (AMPK). However, inhibition of mammalian target of rapamycin, which is a more global metabolic sensor than AMPK, had little effect on inflammation. Similarly, endometrial inflammatory responses to lipopolysaccharide were not affected by insulin-like growth factor-1, which is an endocrine regulator of metabolism. Interestingly, the inflammatory responses to lipopolysaccharide increased endometrial glucose consumption and induced the Warburg effect, which could exacerbate deficits in glucose availability in the tissue. In conclusion, metabolic energy stress perturbed inflammatory responses to pathogen-associated molecular patterns in bovine endometrial tissue, and the most fundamental regulators of cellular energy, glucose availability and AMPK, had the greatest impact on innate immunity.

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          Most cited references32

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          Origin and physiological roles of inflammation.

          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes.

            Cells from some tumors use an altered metabolic pattern compared with that of normal differentiated adult cells in the body. Tumor cells take up much more glucose and mainly process it through aerobic glycolysis, producing large quantities of secreted lactate with a lower use of oxidative phosphorylation that would generate more adenosine triphosphate (ATP), water, and carbon dioxide. This is the Warburg effect, which provides substrates for cell growth and division and free energy (ATP) from enhanced glucose use. This metabolic switch places the emphasis on producing intermediates for cell growth and division, and it is regulated by both oncogenes and tumor suppressor genes in a number of key cancer-producing pathways. Blocking these metabolic pathways or restoring these altered pathways could lead to a new approach in cancer treatments.
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              Nutrient sensing and inflammation in metabolic diseases.

              The proper functioning of the pathways that are involved in the sensing and management of nutrients is central to metabolic homeostasis and is therefore among the most fundamental requirements for survival. Metabolic systems are integrated with pathogen-sensing and immune responses, and these pathways are evolutionarily conserved. This close functional and molecular integration of the immune and metabolic systems is emerging as a crucial homeostatic mechanism, the dysfunction of which underlies many chronic metabolic diseases, including type 2 diabetes and atherosclerosis. In this Review we provide an overview of several important networks that sense and manage nutrients and discuss how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                14 March 2016
                2016
                : 11
                : 3
                : e0151416
                Affiliations
                [1 ]Institute of Life Science, Swansea University Medical School, Singleton Park, Swansea, United Kingdom
                [2 ]Faculty of Veterinary Medicine, Federal University of Uberlândia, Uberlândia, Brazil
                Hull York Medical School, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MLT JGC IMS. Performed the experiments: MLT JGC PGN. Analyzed the data: MLT JGC PGN IMS. Wrote the paper: MLT IMS.

                Article
                PONE-D-16-00776
                10.1371/journal.pone.0151416
                4790959
                26974839
                75379d38-a32b-4411-b093-44fcbe1235ce
                © 2016 Turner 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
                : 7 January 2016
                : 26 February 2016
                Page count
                Figures: 7, Tables: 0, Pages: 20
                Funding
                Doctoral training for MLT was funded by the Biotechnology and Biological Sciences Research Council (BB/F017596/1), and the work was supported in part by a project grant to IMS funded by the Biotechnology and Biological Sciences Research Council (BB/I017240/1). PGN was supported by Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (99999.010219/2014-05) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (486143/2013-9). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Glucose
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Glucose
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Carbohydrate Metabolism
                Glucose Metabolism
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
                Research and Analysis Methods
                Biological Cultures
                Organ Cultures
                Biology and Life Sciences
                Anatomy
                Reproductive System
                Uterus
                Endometrium
                Medicine and Health Sciences
                Anatomy
                Reproductive System
                Uterus
                Endometrium
                Biology and Life Sciences
                Immunology
                Immune Response
                Medicine and Health Sciences
                Immunology
                Immune Response
                Biology and Life Sciences
                Immunology
                Immune System
                Innate Immune System
                Medicine and Health Sciences
                Immunology
                Immune System
                Innate Immune System
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Energy Metabolism
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Energy Metabolism
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Energy Metabolism
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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