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      Molecular mechanism of obesity‐induced ‘metabolic’ tissue remodeling

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          Chronic inflammation is a common molecular basis underlying a variety of chronic diseases. Accumulating evidence has also suggested that chronic inflammation contributes to the pathogenesis of obesity and diabetes, which have been considered as metabolic diseases. For the past several decades, there has been dramatic progress in understanding the underlying mechanism of adipose tissue dysfunction induced by obesity. Tissue remodeling is one of the histological features of chronic inflammation, in which stromal cells dramatically change in number and cell type. Indeed, adipose tissue remodeling is induced by various stromal cells, and results in the impairment of adipose tissue function, such as adipocytokine production and lipid storage, which leads to systemic metabolic disorder. In addition to adipose tissue, the liver is another example of obesity‐induced tissue remodeling. In the present review, we discuss how obesity induces interstitial fibrosis in adipose tissue and the liver, particularly focusing on the role of macrophages.

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          Most cited references 30

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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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              Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI.

              Adipocytes are embedded in a unique extracellular matrix whose main function is to provide mechanical support, in addition to participating in a variety of signaling events. During adipose tissue expansion, the extracellular matrix requires remodeling to accommodate adipocyte growth. Here, we demonstrate a general upregulation of several extracellular matrix components in adipose tissue in the diabetic state, therefore implicating "adipose tissue fibrosis" as a hallmark of metabolically challenged adipocytes. Collagen VI is a highly enriched extracellular matrix component of adipose tissue. The absence of collagen VI results in the uninhibited expansion of individual adipocytes and is paradoxically associated with substantial improvements in whole-body energy homeostasis, both with high-fat diet exposure and in the ob/ob background. Collectively, our data suggest that weakening the extracellular scaffold of adipocytes enables their stress-free expansion during states of positive energy balance, which is consequently associated with an improved inflammatory profile. Therefore, the disproportionate accumulation of extracellular matrix components in adipose tissue may not be merely an epiphenomenon of metabolically challenging conditions but may also directly contribute to a failure to expand adipose tissue mass during states of excess caloric intake.

                Author and article information

                J Diabetes Investig
                J Diabetes Investig
                Journal of Diabetes Investigation
                John Wiley and Sons Inc. (Hoboken )
                01 December 2017
                March 2018
                : 9
                : 2 ( doiID: 10.1111/jdi.2018.9.issue-2 )
                : 256-261
                [ 1 ] Department of Molecular Medicine and Metabolism Research Institute of Environmental Medicine Nagoya University Nagoya Japan
                [ 2 ] Department of Organ Network and Metabolism Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan
                [ 3 ] Department of Molecular Endocrinology and Metabolism Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan
                [ 4 ] Department of Molecular and Cellular Metabolism Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan
                [ 5 ] Department of Medicine and Bioregulatory Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan
                [ 6 ] Japan Agency for Medical Research and Development CREST Tokyo Japan
                Author notes
                [* ] Correspondence

                Takayoshi Suganami

                Tel.: +81‐52‐789‐3881

                Fax: +81‐52‐789‐5047

                E‐mail address: suganami@

                © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 2, Tables: 0, Pages: 6, Words: 4286
                Funded by: Ministry of Education, Culture, Sports, Science and Technology of Japan
                Award ID: 16H05171
                Award ID: 16KT0110
                Award ID: 16K08732
                Award ID: 17K19686
                Award ID: 17H05500
                Funded by: Japan Agency for Medical Research and Development (CREST)
                Funded by: Takeda Science Foundation
                Funded by: Takeda Medical Research Foundation
                Funded by: Joint Usage/Research Program of Medical Research Institute
                Funded by: Tokyo Medical and Dental University
                Review Article
                Review Articles
                Custom metadata
                March 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version= mode:remove_FC converted:04.03.2018

                macrophages, obesity, chronic inflammation


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