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      The Roles of Adipokines, Proinflammatory Cytokines, and Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance in Modest Obesity and Early Metabolic Dysfunction

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          Abstract

          The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.

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          Most cited references 42

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          Obesity is associated with macrophage accumulation in adipose tissue.

          Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.
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            Obesity induces a phenotypic switch in adipose tissue macrophage polarization.

            Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80(+)CD11c(+) population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or "alternatively activated" macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-alpha and iNOS that are characteristic of M1 or "classically activated" macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2-KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-alpha-induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.
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              Diagnosis and classification of diabetes mellitus.

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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
                21 April 2016
                2016
                : 11
                : 4
                Affiliations
                [1 ]Department of Internal medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
                [2 ]Department of Obstetrics and Gynecology, Chungnam National University School of Medicine, Daejeon, Republic of Korea
                [3 ]Department of Pathology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
                [4 ]Department of internal medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
                Universidad Pablo de Olavide, Centro Andaluz de Biología del Desarrollo-CSIC, SPAIN
                Author notes

                Competing Interests: The authors received funding from a commercial source, Korea Otsuka Pharmaceuticals grant. Otsuka Pharmaceuticals grant (BJK) provided support with lab equipment and reagents that greatly enhanced the initial phase of this research. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The author has declared that no competing interests exist.

                Conceived and designed the experiments: JHL BJK HJK MS. Performed the experiments: BRY MJC MJR JL. Analyzed the data: JMK KHJ YEK JL HJK. Contributed reagents/materials/analysis tools: YBK MAL KHL. Wrote the paper: YEK KHL BJK HJK.

                PONE-D-15-51346
                10.1371/journal.pone.0154003
                4839620
                27101398
                © 2016 Kang 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.

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                Figures: 1, Tables: 5, Pages: 14
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                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003725, National Research Foundation of Korea;
                Award ID: 2014R1A1A1006176
                Award Recipient :
                Funded by: Korea Otsuka Pharmaceuticals
                Award Recipient :
                This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science (grant number: 2014R1A1A1006176), and financed with a grant from Korea Otsuka Pharmaceuticals, Republic of Korea. A Korea Otsuka Pharmaceuticals grant (BJK) provided support with lab equipment and reagents that greatly enhanced the initial phase of this research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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