TY - JOUR
T1 - Blockade of sphingosine 1-phosphate receptor 2 signaling attenuates high-fat diet-induced adipocyte hypertrophy and systemic glucose intolerance in mice
AU - Kitada, Yoshihiko
AU - Kajita, Kazuo
AU - Taguchi, Koichiro
AU - Mori, Ichiro
AU - Yamauchi, Masahiro
AU - Ikeda, Takahide
AU - Kawashima, Mikako
AU - Asano, Motochika
AU - Kajita, Toshiko
AU - Ishizuka, Tatsuo
AU - Banno, Yoshiko
AU - Kojima, Itaru
AU - Chun, Jerold
AU - Kamata, Shotaro
AU - Ishii, Isao
AU - Morita, Hiroyuki
N1 - Funding Information:
This work was supported in part by the joint research program of the Institute for Molecular and Cellular Regulation, GunmaUniversity. J.C. was supported by the National Institutes of Health. I.I. was supported by Keio University Special Grantin-Aid for Innovative Collaborative Research Project and Keio Gijuku Fukuzawa Memorial Fund.
Publisher Copyright:
Copyright © 2016 by the Endocrine Society.
PY - 2016/5
Y1 - 2016/5
N2 - Sphingosine 1-phosphate (S1P) is known to regulate insulin resistance in hepatocytes, skeletal muscle cells, and pancreatic -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 testsandhadsmaller 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.
AB - Sphingosine 1-phosphate (S1P) is known to regulate insulin resistance in hepatocytes, skeletal muscle cells, and pancreatic -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 testsandhadsmaller 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.
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U2 - 10.1210/en.2015-1768
DO - 10.1210/en.2015-1768
M3 - Article
AN - SCOPUS:84969872555
SN - 0013-7227
VL - 157
SP - 1839
EP - 1851
JO - Endocrinology
JF - Endocrinology
IS - 5
ER -
