Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes

Abstract

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic β cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). FFA, which accumulate in these tissues, are metabolized as lipid derivatives such as ceramide, and the ectopic accumulation of the latter has been shown to lead to lipotoxicity. Ceramide is an active lipid that inhibits the insulin signaling pathway as well as inducing pancreatic β cell death. In mammals, ceramide is a key lipid intermediate for sphingolipid metabolism as is sphingosine-1-phosphate (S1P). S1P levels have also been associated with the development of obesity and T2D. In this review, the current knowledge on S1P metabolism in regulating insulin signaling in pancreatic β cell fate and in the regulation of feeding by the hypothalamus in the context of obesity and T2D is summarized. It demonstrates that S1P can display opposite effects on insulin sensitive tissues and pancreatic β cells, which depends on its origin or its degradation pathway.

Keywords: Sphingosine-1-phosphate; hypothalamus; insulin resistance; obesity; pancreatic β cell fate; type 2 diabetes.

Figure 1

Sphingosine-1-phosphate metabolism in mammals. Sphingolipid de novo synthesis is initiated in the endoplasmic reticulum (ER), starting by the condensation of serine and palmitoyl-coA followed by a cascade of enzymatic reactions to produce ceramide. In the ER, ceramide is deacylated by neutral CDase into sphingosine. Sphingosine is phosphorylated to produce S1P by SphK1/2. Produced S1P can be either dephosphorylated back to sphingosine by ER resident SPPs, or irreversibly transformed into hexadecenal and phosphoethanolamine by S1P lyase. Ceramide is transported to the Golgi apparatus to be transformed into SM, which will reach the plasma membrane. In the plasma membrane, SM can be transformed into ceramide through the action of SMases. Ceramide will then be deacylated by acidic CDase to give sphingosine that will be phosphorylated into S1P by SphK1. Produced S1P can be dephosphorylated by ecto-LPPs. S1P can also be secreted through ABC, SPNS2, and MFSD2B transporters in extracellular space to activate S1P receptors. Extracellular S1P can also be transported by either albumin or ApoM/HDL. The latter can activate S1P receptors. SM can be endocytosed to be recycled into ceramide and sphingosine inside lysosomes. SphK2 can catalyze S1P production in the mitochondria and the nucleus. ABC: ATP-binding cassette. CDase: ceramidase. ER: endoplasmic reticulum. HDL: high density lipoproteins. MFSD2B: Major Facilitator Superfamily Domain Containing 2B. S1P: sphingosine-1-phosphate. SM: sphingomyelin. SMase: sphingomyelinase. SphK: sphingosine kinase. S1P1-5: S1P receptor 1 to 5. SPNS2: Spinster homolog 2. SPP: Sphingosine-1-phosphate phosphohydrolase.

Figure 2

Role of S1P metabolism on insulin in peripheral tissues in response to palmitate. In hepatocytes, palmitate increases intracellular S1P content through SphK1/2 activities. According to studies, produced S1P seems to exert a direct positive action on insulin signaling, or a negative action by stimulating its S1P2 receptors. In muscle cells, palmitate increased intracellular S1P through SphK1 activity, which favors Akt activation, glucose uptake, and glycogen synthesis in response to insulin. In adipocytes, palmitate increases intracellular S1P to inhibit Akt activation in response to insulin. Produced S1P also favors expression of pro-inflammatory cytokines that will contribute to inhibit Akt activity. CDase: ceramidase. GLUT4: glucose transporter 4. IRS: insulin receptor substrate. PI3K: phosphatidylinositol-3-kinase. SphK: sphingosine kinase. S1P2: S1P receptor 2.

Figure 3

Role of S1P metabolism on pancreatic β cell fate. In pancreatic β cells, cytokines, such as IL1β increase SphK1 expression and repress SPL expression. This contributes to the increase of intracellular S1P content and apoptosis. In contrast, extracellular ApoM/HDL-bound S1P y antagonizes apoptosis induced by IL1β. In pancreatic β cells, palmitate increases the expression of both SphK1 and2. SphK1 activation represses palmitate-induced pancreatic β cell apoptosis, whereas SphK2 activation promotes apoptosis. SphK1-produced S1P can be secreted and stimulates S1P2 to promote apoptosis. High glucose levels could activate both SphK1 and 2, which contribute to the secretion of insulin. CDase: ceramidase. SPL: S1P lyase. SphK: sphingosine kinase. S1P2: S1P receptor 2.