PMID- 26977813 OWN - NLM STAT- MEDLINE DCOM- 20160726 LR - 20220410 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 3 DP - 2016 TI - Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction. PG - e0151511 LID - 10.1371/journal.pone.0151511 [doi] LID - e0151511 AB - 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. FAU - Komiya, Chikara AU - Komiya C AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Tsuchiya, Kyoichiro AU - Tsuchiya K AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Shiba, Kumiko AU - Shiba K AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Miyachi, Yasutaka AU - Miyachi Y AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Furuke, Shunsaku AU - Furuke S AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Shimazu, Noriko AU - Shimazu N AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Yamaguchi, Shinobu AU - Yamaguchi S AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Kanno, Kazuo AU - Kanno K AD - Kanno Clinic, Tokyo, Japan. FAU - Ogawa, Yoshihiro AU - Ogawa Y AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. AD - Japan Agency for Medical Research and Development, CREST, Tokyo, Japan. LA - eng PT - Journal Article PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20160315 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Glucosides) RN - 0 (Hypoglycemic Agents) RN - 0 (Leptin) RN - 0 (Lipids) RN - 0 (SLC5A2 protein, human) RN - 0 (Slc5a2 protein, mouse) RN - 0 (Sodium-Glucose Transporter 2) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Thiophenes) RN - 3N2N8OOR7X (ipragliflozin) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Adipose Tissue/drug effects/metabolism MH - Adult MH - Animals MH - Body Weight/drug effects MH - Diabetes Mellitus, Type 2/complications/*drug therapy MH - Diet, High-Fat/adverse effects MH - Drug Evaluation, Preclinical MH - Energy Intake/drug effects MH - Epididymis/drug effects/metabolism MH - Glucose/metabolism MH - Glucosides/pharmacology/*therapeutic use MH - Humans MH - Hyperphagia/chemically induced MH - Hypoglycemic Agents/pharmacology/*therapeutic use MH - Insulin Resistance MH - Leptin/deficiency MH - Lipids/analysis MH - Liver/drug effects/metabolism/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Obese MH - Non-alcoholic Fatty Liver Disease/*drug therapy/etiology/prevention & control MH - Obesity/*complications MH - Organ Size/drug effects MH - Sodium-Glucose Transporter 2 MH - Sodium-Glucose Transporter 2 Inhibitors MH - Thiophenes/pharmacology/*therapeutic use MH - Weight Loss PMC - PMC4792392 COIS- 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. EDAT- 2016/03/16 06:00 MHDA- 2016/07/28 06:00 PMCR- 2016/03/15 CRDT- 2016/03/16 06:00 PHST- 2015/12/04 00:00 [received] PHST- 2016/02/29 00:00 [accepted] PHST- 2016/03/16 06:00 [entrez] PHST- 2016/03/16 06:00 [pubmed] PHST- 2016/07/28 06:00 [medline] PHST- 2016/03/15 00:00 [pmc-release] AID - PONE-D-15-52589 [pii] AID - 10.1371/journal.pone.0151511 [doi] PST - epublish SO - PLoS One. 2016 Mar 15;11(3):e0151511. doi: 10.1371/journal.pone.0151511. eCollection 2016.