title: Tofogliflozin Improves Insulin Resistance in Skeletal Muscle and Accelerates Lipolysis in Adipose Tissue in Male Mice.
abstract: Sodium glucose cotransporter 2 inhibitors have attracted attention as they exert antidiabetic and antiobesity effects. In this study, we investigated the effects of tofogliflozin on glucose homeostasis and its metabolic consequences and clarified the underlying molecular mechanisms. C57BL/6 mice were fed normal chow containing tofogliflozin (0.005%) for 20 weeks or a high-fat diet containing tofogliflozin (0.005%) for 8 weeks ad libitum. In addition, the animals were pair-fed in relation to controls to exclude the influence of increased food intake. Tofogliflozin reduced the body weight gain, mainly because of fat mass reduction associated with a diminished adipocyte size. Glucose tolerance and insulin sensitivity were ameliorated. The serum levels of nonesterified fatty acid and ketone bodies were increased and the respiratory quotient was decreased in the tofogliflozin-treated mice, suggesting the acceleration of lipolysis in the white adipose tissue and hepatic β-oxidation. In fact, the phosphorylation of hormone-sensitive lipase and the adipose triglyceride lipase protein levels in the white adipose tissue as well as the gene expressions related to β-oxidation, such as Cpt1α in the liver, were significantly increased. The hepatic triglyceride contents and the expression levels of lipogenic genes were decreased. Pair-fed mice exhibited almost the same results as mice fed an high-fat diet ad libitum. Moreover, a hyperinsulinemic-euglycemic clamp revealed that tofogliflozin improved insulin resistance by increasing glucose uptake, especially in the skeletal muscle, in pair-fed mice. Taken together, these results suggest tofogliflozin ameliorates insulin resistance and obesity by increasing glucose uptake in skeletal muscle and lipolysis in adipose tissue.
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Obata
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Iseki
authors.initials: I
authors.lastname: Takamoto
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Katsuyama
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukazawa
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Sachiya
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Kaito
authors.initials: K
authors.lastname: Iwayama
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Kumpei
authors.initials: K
authors.lastname: Tokuyama
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.affiliation: Department of Diabetes and Metabolic Diseases (A.O., N.K., T.Ku., M.I., H.S., Y.Sa., I.T., H.K., K.U., T.Ka.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (N.K., T.Ka.), The University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program (N.K., T.Ku.), National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory for Metabolic Homeostasis (N.K., T.Ku.), Research Center of Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Division of Cardiovascular Medicine (T.Ku.), Toho University, Ohashi Hospital, Tokyo 153-8515, Japan; Research Division (Y.Su., M.F., S.I.), Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka 412-8513, Japan; and Graduate School of Comprehensive Human Science (K.I., K.T.), University of Tsukuba, Tsukuba 305-8577, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D059305:Diet, High-Fat; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005960:Glucosides / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D007657:Ketone Bodies / Q000097:blood; D008049:Lipase / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008066:Lipolysis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D002787:Sterol Esterase / Q000187:drug effects / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects; D000217:Acyltransferases
chemical_list: D001559:Benzhydryl Compounds; D005230:Fatty Acids, Nonesterified; D005947:Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D007657:Ketone Bodies; D008049:Lipase; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D002787:Sterol Esterase; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases; C575086:6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol