Modulation of the expression of sphingosine 1-phosphate 2 receptors regulates the differentiation of pre-adipocytes

Abstract

Abstract. Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator that regulates multiple signals through S1P receptors responsible for biological responses. In particular, the S1P 2 receptor has distinct roles in the S1P-mediated differentiation of certain cell types. The present study was the first, to the best of our knowledge, to report the role of the S1P 2 receptor in the adipocyte differentiation of 3T3-L1 pre-adipocytes. In order to investigate the influence of S1P 2 receptors in the anti-adipogenic effects of S1P, S1P 2 receptor silencing and overexpression of were used. S1P 2 overexpression with adenoviral vectors inhibited adipogenesis and inhibited the expression of peroxisome proliferator-activated receptor γ (PPARγ), adiponectin and CCAAT/enhancer binding protein-α, which were upregulated following incubation in differentiation media. Furthermore, S1P completely lost its ability to impair adipogenic differentiation following silencing of S1P 2 . Silencing of the S1P 2 receptor additionally blocked the downregulation of PPARγ protein and phospho-c-Jun N-terminal kinase protein induced by S1P treatment. In conclusion, the present study demonstrated that the S1P 2 receptor is a key signaling molecule in the S1P-dependent inhibition of adipogenic differentiation and additionally suggested that selective targeting of S1P 2 receptors may have clinical applications for the treatment of obesity.

Sphingosine-1-phosphate (S1P) regulates adipogenesis and systemic insulin sensitivity

“…Our result that S1pr2 signal attenuated adipogenesis was consisted with that of Moon et al [10]. On the other hand, Jeong et al, despite performing the same experiment as ours to silencing S1pr2 with siRNA in 3T3-L1 adipocytes, obtained the opposite result to ours that adipogenesis was accelerated [11]. We cannot explain this discrepancy now.…”

Targeting ceramide metabolism in obesity

“…As mentioned previously in Modulating Ceramide Metabolism to Prevent and/or Reverse Obesity-Related Disease, it has been demonstrated that activation of SphK1 to enhance flux of ceramide into S1P may also protect against obesity-induced insulin resistance, and recent studies have also suggested that S1P may possess additional salutary actions against obesity-related metabolic dysfunction (13). These salutary actions of S1P against the obesity phenotype include inhibition of adipocyte differentiation (57,73) and promoting survival of cardiac myocytes following exposure to hypoxia (124). Hence, ceramide/sphingolipid metabolism is intricate and complex and possesses multiple nodes at which its specific metabolites/intermediates can influence various aspects of obesity-associated metabolic dysfunction.…”

Ceramide and sphingosine 1-phosphate in adipose dysfunction

“…↑ P-ERK ↑ adipocyte proliferation [199] 3T3-F442A adipocyte VPC-23019 (10µM, 5 d) ↑ adipocyte-specific gene expression (Fabp4, Lpl, Adipoq) ↑ adipogenic differentiation [199] 3T3-L1 adipocytes siRNA S1P2 ↓ S1P-induced downregulation of PPARγ and P-JNK ↓ S1P-mediated inhibition of lipid accumulation [200] 3T3-L1 adipocytes DMS [199]…”

“…pre-adipocytes inhibits the JNK pathway and induces down-regulation of PPARγ expression [200]. S1P also increases the expression of S1P2 during the differentiation of 3T3-L1 preadipocytes and this is associated with the inhibition of adipogenesis and lipid accumulation [198].…”