title: Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction.
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.
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Komiya
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kyoichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Shiba
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Miyachi
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Furuke
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Shimazu
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Kanno Clinic, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kanno
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Japan Agency for Medical Research and Development, CREST, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D059305:Diet, High-Fat / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D002149:Energy Intake / Q000187:drug effects; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006963:Hyperphagia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D020738:Leptin / Q000172:deficiency; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D009765:Obesity / Q000150:complications*; D009929:Organ Size / Q000187:drug effects; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*; D015431:Weight Loss
chemical_list: D005960:Glucosides; D007004:Hypoglycemic Agents; D020738:Leptin; D008055:Lipids; C089180:SLC5A2 protein, human; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C572941:ipragliflozin; D005947:Glucose