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.

Steroidogenic Acute Regulatory Protein (StAR) Overexpression Reduces Inflammation and Insulin Resistance in Obese Mice

“…Insulin resistance has been proven as a critical factor that links metabolic diseases to obesity [Kitada et al, 2016]. Insulin resistance has been proven as a critical factor that links metabolic diseases to obesity [Kitada et al, 2016].…”

Ganglioside GM3 content in skeletal muscles is increased in type 2 but decreased in type 1 diabetes rat models: Implications of glycosphingolipid metabolism in pathophysiology of diabetes

“…Muscle‐related insulin resistance caused by ceramide could be prevented by sphingosine kinase 1 (SK1), in part by promoting sphingosine incorporation into sphingosine‐1‐phosphate (S1P), but not into Cer (which is composed of sphingosine and fatty acid) . A recent study found that blockade of S1P receptor 2 signaling attenuated adipocyte hypertrophy and systemic glucose intolerance in mice fed an HFD . Without insulin being secreted, there is an absence of lipolysis suppression, which increases plasma free fatty acid (FFA) levels .…”

“…41 A recent study found that blockade of S1P receptor 2 signaling attenuated adipocyte hypertrophy and systemic glucose intolerance in mice fed an HFD. 42 Without insulin being secreted, there is an absence of lipolysis suppression, which increases plasma free fatty acid (FFA) levels. 43,44 Fox et al 45 showed that plasma levels of a bioactive sphingolipid metabolite formed by the phosphorylation of sphingosine, namely S1P, were markedly elevated, whereas levels of ω9 24:1 acid (nervonic acid) were reduced in T1DM rat models with concomitant decreases in plasma concentrations of 24:1-esterified sphingolipids (i.e.…”

Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

“…Levels of plasminogen activator inhibitor-1, which is produced from adipocytes, are increased in obese individuals. Interestingly, JTE-013 suppressed plasminogen activator inhibitor-1 increases in mouse 3T3-L1 adipocytes (Ito et al ., 2013), and S1P 2 deficient mice fed a high-fat diet had better glucose/insulin tolerance test results and smaller epididymal adipocytes (Kitada et al ., 2016). These results suggest JTE-013 might be useful for treating obesity and type 2 diabetes.…”