title: Blockade of Sphingosine 1-Phosphate Receptor 2 Signaling Attenuates High-Fat Diet-Induced Adipocyte Hypertrophy and Systemic Glucose Intolerance in Mice.
abstract: Sphingosine 1-phosphate (S1P) is known to regulate insulin resistance in hepatocytes, skeletal muscle cells, and pancreatic β-cells. Among its 5 cognate receptors (S1pr1-S1pr5), S1P seems to counteract insulin signaling and confer insulin resistance via S1pr2 in these cells. S1P may also regulate insulin resistance in adipocytes, but the S1pr subtype(s) involved remains unknown. Here, we investigated systemic glucose/insulin tolerance and phenotypes of epididymal adipocytes in high-fat diet (HFD)-fed wild-type and S1pr2-deficient (S1pr2(-/-)) mice. Adult S1pr2(-/-) mice displayed smaller body/epididymal fat tissue weights, but the differences became negligible after 4 weeks with HFD. However, HFD-fed S1pr2(-/-) mice displayed better scores in glucose/insulin tolerance tests and had smaller epididymal adipocytes that expressed higher levels of proliferating cell nuclear antigen than wild-type mice. Next, proliferation/differentiation of 3T3-L1 and 3T3-F442A preadipocytes were examined in the presence of various S1pr antagonists: JTE-013 (S1pr2 antagonist), VPC-23019 (S1pr1/S1pr3 antagonist), and CYM-50358 (S1pr4 antagonist). S1P or JTE-013 treatment of 3T3-L1 preadipocytes potently activated their proliferation and Erk phosphorylation, whereas VPC-23019 inhibited both of these processes, and CYM-50358 had no effects. In contrast, S1P or JTE-013 treatment inhibited adipogenic differentiation of 3T3-F442A preadipocytes, whereas VPC-23019 activated it. The small interfering RNA knockdown of S1pr2 promoted proliferation and inhibited differentiation of 3T3-F442A preadipocytes, whereas that of S1pr1 acted oppositely. Moreover, oral JTE-013 administration improved glucose tolerance/insulin sensitivity in ob/ob mice. Taken together, S1pr2 blockade induced proliferation but suppressed differentiation of (pre)adipocytes both in vivo and in vitro, highlighting a novel therapeutic approach for obesity/type 2 diabetes.
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kitada
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kajita
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Mori
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamauchi
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Kawashima
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Motochika
authors.initials: M
authors.lastname: Asano
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Kajita
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ishizuka
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Banno
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Kojima
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Kamata
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Ishii
authors.affiliation: Department of General Internal Medicine (Y.K., K.K., K.T., I.M., M.Y., T.Ik., M.K., M.A., T.K., H.M.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of General Internal Medicine and Rheumatology (T.Is.), Gifu Municipal Hospital, Gifu 500-8513, Japan; Department of Dermatology (Y.B.), Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Laboratory of Cell Physiology (I.K.), Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; Molecular and Cellular Neuroscience Department (J.C.), Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037; and Department of Biochemistry (S.K., I.I.), Keio University Graduate School of Pharmaceutical Sciences, Tokyo 105-8512, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Morita
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D049108:Cell Enlargement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D059305:Diet, High-Fat; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010768:Phosphoserine / Q000031:analogs & derivatives / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: C471998:JTE 013; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C000611541:VPC23019; C533955:sphingosine-1-phosphate receptor-2, mouse; D010768:Phosphoserine