1648-P: Opposing Roles of Sphingosine 1 Phosphate Receptors 1 and 2 in Fat Deposition and Glucose Tolerance in Obese Male Mice

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation through five cognate G protein-coupled receptors (S1P₁-S1P₅). However, little is known about the role of S1P in obesity formation. We previously demonstrated that blockade of S1P₂ signaling in S1P₂-deficient mice attenuates high-fat diet-induced adipocyte hypertrophy and glucose intolerance and a S1P₂-specific antagonist JTE-013 inhibits, whereas an S1P₁/S1P₃ dual antagonist (VPC23019) activates adipogenic differentiation. In this study, we examined whether an S1P₁-specific agonist SEW-2871 and VPC23019 act on obesity and glucose intolerance in ob/ob mice. The oral administration of SEW-2871 and JTE-013 induced significant reductions in body weight gains and epididymal/inguinal fat adipocyte sizes and improved glucose intolerance and adipocyte inflammation in ob/ob mice but not in their control C57BL/6J mice. Both SEW-2871 and JTE-013 decreased mRNA levels of tumor necrosis factor-α and CD11c, whereas increased those of CD206 and adiponectin in the epididymal (not inguinal) fats isolated from ob/ob mice but not in control mice with no changes in the levels of peroxisome proliferator activated receptor gamma and its regulated genes. By contrast, VPC23019 did not cause all such alterations in these mice, however co-administration of SEW-2871 and VPC23019 abolished the effect of SEW-2871 on ob/ob mice.

In conclusion, the S1P₁ agonist SEW-2871 acted like the S1P₂ antagonist JTE-013 to reduce body and improve glucose tolerance in obese mice. Therefore, endogenous S1P could promote obesity/type 2 diabetes through the S1P₂, whereas exogenous S1P could act against them through the S1P₁.