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      Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction

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          Abstract

          Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient ( ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.

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          Most cited references21

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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.
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            Adipocyte death, adipose tissue remodeling, and obesity complications.

            We sought to determine the role of adipocyte death in obesity-induced adipose tissue (AT) inflammation and obesity complications. Male C57BL/6 mice were fed a high-fat diet for 20 weeks to induce obesity. Every 4 weeks, insulin resistance was assessed by intraperitoneal insulin tolerance tests, and epididymal (eAT) and inguinal subcutaneous AT (iAT) and livers were harvested for histological, immunohistochemical, and gene expression analyses. Frequency of adipocyte death in eAT increased from <0.1% at baseline to 16% at week 12, coincident with increases in 1) depot weight; 2) AT macrophages (ATM Phi s) expressing F4/80 and CD11c; 3) mRNA for tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1, and interleukin (IL)-10; and 4) insulin resistance. ATM Phi s in crown-like structures surrounding dead adipocytes expressed TNF-alpha and IL-6 proteins. Adipocyte number began to decline at week 12. At week 16, adipocyte death reached approximately 80%, coincident with maximal expression of CD11c and inflammatory genes, loss (40%) of eAT mass, widespread collagen deposition, and accelerated hepatic macrosteatosis. By week 20, adipocyte number was restored with small adipocytes, coincident with reduced adipocyte death (fourfold), CD11c and MCP-1 gene expression (twofold), and insulin resistance (35%). eAT weight did not increase at week 20 and was inversely correlated with liver weight after week 12 (r = -0. 85, P < 0.001). In iAT, adipocyte death was first detected at week 12 and remained
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              Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways.

              Through unknown mechanisms, insulin activates the sterol regulatory element-binding protein (SREBP1c) transcription factor to promote hepatic lipogenesis. We find that this induction is dependent on the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). To further define the role of mTORC1 in the regulation of SREBP1c in the liver, we generated mice with liver-specific deletion of TSC1 (LTsc1KO), which results in insulin-independent activation of mTORC1. Surprisingly, the LTsc1KO mice are protected from age- and diet-induced hepatic steatosis and display hepatocyte-intrinsic defects in SREBP1c activation and de novo lipogenesis. These phenotypes result from attenuation of Akt signaling driven by mTORC1-dependent insulin resistance. Therefore, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. Copyright © 2011 Elsevier Inc. All rights reserved.
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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
                15 March 2016
                2016
                : 11
                : 3
                : e0151511
                Affiliations
                [1 ]Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
                [2 ]Kanno Clinic, Tokyo, Japan
                [3 ]Japan Agency for Medical Research and Development, CREST, Tokyo, Japan
                Cincinnati Children's Hospital Medical Center, UNITED STATES
                Author notes

                Competing Interests: The authors of this manuscript have the following competing interests: CK reports non-financial support from Astellas Pharma Inc., grants from Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. KT reports non-financial support from Astellas Pharma Inc., grants from Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study; grants from Astellas Pharma Inc., grants from Novartis Pharma K.K., grants from Daiichi Sankyo Company Limited., grants and personal fees from AstraZeneca K.K., grants and personal fees from Nippon Boehringer Ingelheim Co., Ltd., grants and personal fees from MSD K.K., grants and personal fees from Takeda Pharmaceutical Compamy Limited., personal fees from Kissei Pharmaceutical Co., Ltd., grants from Sanofi K.K., personal fees from Novo Nordisk Pharma Ltd., grants and personal fees from Lilly Japan K.K., personal fees from Ono Pharmaceutical Co., Ltd., grants from Mochida Pharmaceutical Co., LTD., grants from Terumo Co., Ltd., outside the submitted work. KS reports non-financial support from Astellas Pharma Inc., grants from Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. YM reports non-financial support from Astellas Pharma Inc., grants from Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. SF reports non-financial support from Astellas Pharma Inc., grants from Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. NS reports non-financial support from Astellas Pharma Inc., grants from Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. SY reports non-financial support from Astellas Pharma Inc., grants from Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. KK reports other from Astellas Pharma Inc., during the conduct of the study; personal fees from Astellas Pharma Inc., personal fees from Johnson & Johnson K.K., personal fees from Novartis Pharma K.K., personal fees from Kowa Pharmaceutical Company LTD., personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from Daiichi Sankyo Company Limited., personal fees from AstraZeneca K.K., personal fees from Taisho Toyama Pharmaceutical Co., Ltd., personal fees from Nippon Boehringer Ingelheim Co., Ltd., personal fees from MSD K.K., personal fees from Takeda Pharmaceutical Compamy Limited., personal fees from Kissei Pharmaceutical Co., Ltd., personal fees from Sanofi K.K., personal fees from Novo Nordisk Pharma Ltd., personal fees from Lilly Japan K.K., personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from Shionogi & Co., Ltd, personal fees from Ono Pharmaceutical Co., Ltd., outside the submitted work. YO reports non-financial support from Astellas Pharma Inc., grants from Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study; grants from Astellas Pharma Inc., grants from Novartis Pharma K.K., grants from AstraZeneca K.K., grants from Nippon Boehringer Ingelheim Co., Ltd., grants from MSD K.K., grants from Takeda Pharmaceutical Compamy Limited., grants from Kissei Pharmaceutical Co., Ltd., grants from Sanofi K.K., grants from Lilly Japan K.K., grants from Ono Pharmaceutical Co., Ltd., grants from Mochida Pharmaceutical Co., Ltd., grants from TERUMO CORPORATION, grants from JCR Pharmaceuticals Co., Ltd, grants from ASKA Pharmaceutical Co., Ltd., grants from Eisai Co., Ltd., grants from NIPRO Co., Ltd., grants from Nestle Japan Limited, grants from Pfizer Japan Inc., grants from Shionogi & Co., Ltd., grants from THERAVALUES CORPORATION, grants from Kyowa Hakko Kirin Co,. Ltd., grants from Kowa Pharmaceutical Co., Ltd., grants from Taisho Toyama Pharmaceutical Co., Ltd., grants from TEIJIN PHARMA LIMITED, grants from Mitsubishi Tanabe Pharma Corporation, outside the submitted work. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: CK KT KK YO. Performed the experiments: CK KT KS YM SF NS SY KK. Analyzed the data: CK KT. Wrote the paper: CK KT YO.

                Article
                PONE-D-15-52589
                10.1371/journal.pone.0151511
                4792392
                26977813
                b5b32c8b-de1a-4d45-8715-2bbac437a124
                © 2016 Komiya 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
                : 4 December 2015
                : 29 February 2016
                Page count
                Figures: 5, Tables: 2, Pages: 19
                Funding
                This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Ipragliflozin was provided by Astellas Pharma Inc. The clinical study at Kanno clinic was financially supported by Astellas Pharma Inc. 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
                Physiology
                Physiological Parameters
                Body Weight
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Fatty Liver
                Biology and Life Sciences
                Biochemistry
                Lipids
                Fats
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Anatomical Pathology
                Cytopathology
                Steatosis
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Biology and Life Sciences
                Biochemistry
                Lipids
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Connective Tissue Cells
                Adipocytes
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Connective Tissue Cells
                Adipocytes
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
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                Custom metadata
                The anonymized and de-identified clinical dataset is available upon request. All other relevant data are within the paper and its Supporting Information files.

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