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

Abstract

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). 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 of preadipocytes. Based on those observations, this study examined whether an S1P1-specific agonist SEW-2871, VPC23019, or their combination act on obesity and glucose intolerance in leptin-deficient ob/ob mice. The oral administration of SEW-2871 or JTE-013 induced significant reductions in body/epididymal fat 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 fats isolated from ob/ob 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 but counteracted with all those SEW-2871 actions in these mice. In conclusion, the S1P1 agonist SEW-2871 acted like the S1P2 antagonist JTE-013 to reduce body/epididymal fats and improve glucose tolerance in obese mice. Therefore, this study raises the possibility that endogenous S1P could promote obesity/type 2 diabetes through the S1P2, whereas exogenous S1P could act against them through the S1P1.

Sphingosine 1-Phosphate Regulates Obesity and Glucose Homeostasis

“…Reduced plasma and adipose tissue S1P levels in SphK1 −/− mice improved insulin resistance, which is associated with reducing adipocyte hypertrophy and inflammation in adipose tissue [96]. Our observations that either S1P 1 activation or S1P 2 blockage ameliorated adipocyte hypertrophy, glucose intolerance, and inflammation in the VAT of obese mice [1,2] were consistent with previous results showing that apoM-carrying S1P worked through S1P 1/3 to improve insulin resistance, whereas albumin-carrying S1P activated S1P 2 to exacerbate it in obese adipocytes (Figure 2) [110,132] and the liver [106]. Hepatic insulin resistance is caused by the accumulation of ceramide and its metabolite, sphingosine [103,104,107].…”

“…Administration of JTE-013 or SEW-2871 for 12 weeks reduced body weight gain and adipocyte size in both epididymal and inguinal adipose tissues of ob/ob mice [2], and improved glucose intolerance and inflammation in epididymal adipose tissue (but not hepatic steatosis); however, all SEW-2871 effects were canceled by co-administration with VPC-23019 [2]. Consistent with the results in HFD-fed S1P 2 −/− mice [1], preventing adipose tissue inflammation and glucose intolerance using JTE-013 and SEW-2871 was attributed to reducing adipocyte size rather than weight loss.…”

“…Systemic genetic deletion of S1P 3 exacerbated HFD-induced hepatic steatosis [109]. In contrast, oral administration of JTE-013 (an S1P 2 antagonist) and SEW-2871 (an S1P 1 agonist) failed to alleviate hepatic steatosis [2]. In HFD-induced obese mice, the levels of plasma S1P and its carrier, apoM, were upregulated.…”

“…Nextgeneration S1PR modulators with fewer adverse effects and receptor specificities, including mocravimod (S1P 1/4/5 agonist), ozanimod (S1P 1/5 agonist), etrasimod (S1P 1/4/5 agonist), amiselimod (S1P 1 agonist), ponesimod (S1P 1/4/5 agonist), siponimod (S1P 1/5 agonist), and ceralifimod (S1P 1/5 agonist), were developed and investigated for clinical application in diseases other than multiple sclerosis, including inflammatory bowel disease, psoriasis, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, and certain cancers [87]. In the laboratory, SEW-2871 has been used as a S1P 1 agonist, VPC-23019 as a S1P 1/3 antagonist, JTE-013 as a S1P 2 antagonist, and CYM-50358 as a S1P 4 antagonist [1,2].…”

“…Among the numerous candidates, a few researchers have focused on sphingolipid-derived mediators such as sphingosine 1-phosphate (S1P) and ceramide, which have potent and diverse physiological properties. In this review, we summarize the biological roles of S1P/ceramide in obesity and insulin signaling and discuss the prospects of S1P receptor (S1PR) agonists for use as therapeutics, partly based on our results [1,2], where obesity and T2DM could be treated by modulating specific S1PR signaling. Additionally, there is accumulating evidence showing the roles of S1P/S1PR in the onset and progression of NAFLD and hepatic fibrosis [3][4][5].…”