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Review
. 2024 Jan 11;25(2):932.
doi: 10.3390/ijms25020932.

Sphingosine 1-Phosphate Regulates Obesity and Glucose Homeostasis

Kazuo Kajita  1 , Isao Ishii  2 , Ichiro Mori  3 , Motochika Asano  3 , Masayuki Fuwa  3 , Hiroyuki Morita  3
Affiliations
Review

Sphingosine 1-Phosphate Regulates Obesity and Glucose Homeostasis

Kazuo Kajita et al. Int J Mol Sci. .

Abstract

One of the major global health and welfare issues is the treatment of obesity and associated metabolic disorders, such as type 2 diabetes mellitus and nonalcoholic fatty liver disease. Obesity, caused by the excessive accumulation of triglycerides in adipose tissues, induces adipocyte dysfunction, followed by inflammation, in adipose tissues and lipotoxicity in nonadipose tissues. Several studies have shown that obesity and glucose homeostasis are influenced by sphingolipid mediators, including ceramide and sphingosine 1-phosphate (S1P). Cellular accumulation of ceramide impairs pancreatic β-cell survival, confers insulin resistance in the liver and the skeletal muscle, and deteriorates adipose tissue inflammation via unknown molecular mechanisms. The roles of S1P are more complicated, because there are five cell-surface S1P receptors (S1PRs: S1P1-5) which have altered functions, different cellular expression patterns, and inapparent intracellular _targets. Recent findings, including those by our group, support the notable concept that the pharmacological activation of S1P1 or S1P3 improves obesity and associated metabolic disorders, whereas that of S1P2 has the opposite effect. In addition, the regulation of S1P production by sphingosine kinase (SphK) is an essential factor affecting glucose homeostasis. This review summarizes the current knowledge on SphK/S1P/S1PR signaling in and against obesity, insulin resistance, and associated disorders.

Keywords: S1P receptor; adipocyte; adipogenesis; ceramide; glucose tolerance; inflammation; insulin resistance; lipotoxicity; sphingosine 1-phospahte; sphingosine kinase.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Systemic insulin resistance and lipotoxic damage caused by excessive lipid accumulation in both adipose and nonadipose tissues [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47].
Figure 2
Figure 2
Sphingosine 1-phosphate (S1P) production and associated cell surface receptor signaling that regulates adipose function. Ceramide is produced from sphingomyelin by sphingomyelinase (SMase) or from palmitoyl-CoA and serine via serine palmitoyltransferase (Sptlc), 3-ketosphinganine reductase (KSR), ceramide synthase (CerS), and dihydroceramide desaturase (DES). Ceramide is converted to sphingosine by ceramidase (CDase) and S1P by SphK1/2. S1P acts through intracellular _targets (HDAC1/2, PHB2, etc.) or is secreted extracellularly (e.g., in circulation) to affect cell surface S1P receptors (S1P1–S1P5). S1P1/3 agonists and S1P2 agonists/ceramide have opposing actions in terms of adipose function: the former prevents obesity and associated adipogenesis, adipocyte inflammation, and insulin resistance, whereas the latter rather promotes such conditions [1,2].
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