S1P/S1PR3 signalling axis protects against obesity-induced metabolic dysfunction

Area of Science:

• Metabolic disease
• Endocrinology
• Lipid signaling

Background:

• Sphingosine-1-phosphate (S1P) is a bioactive lipid regulating cell growth, immune cell trafficking, and inflammation via G-protein coupled receptors (S1PR1-5).
• Type 2 diabetes (T2D) is a metabolic disorder characterized by impaired glucose homeostasis and inflammation.

Purpose of the Study:

• To investigate the role of S1P and its receptor S1PR3 in metabolic regulation, particularly in the context of Type 2 diabetes and obesity.
• To explore the therapeutic potential of S1P in improving metabolic parameters.

Main Methods:

• Analysis of plasma S1P levels in Type 2 diabetic subjects treated with rosiglitazone.
• Gene expression analysis of S1PR3 in adipose tissue and liver of mice fed a high-fat diet (HFD).
• Phenotypic characterization of S1PR3 knockout (S1PR3-/-) mice on an HFD, including metabolic assessments and immune cell profiling.
• Investigation of S1P effects on adipogenesis and PPARγ expression in 3T3-L1 preadipocytes.

Main Results:

• Plasma S1P levels increased with rosiglitazone treatment in T2D subjects, correlating with improved glucose homeostasis.
• HFD-induced obesity increased S1PR3 expression in adipose tissue and liver.
• S1PR3-/- mice on HFD exhibited partial lipodystrophy, exacerbated insulin resistance, glucose intolerance, adipose and hepatic inflammation, and hepatic steatosis.
• S1P promoted adipogenesis and S1P-S1PR3 signaling regulated PPARγ expression in preadipocytes.

Conclusions:

• S1P exerts anti-diabetic effects and improves glucose homeostasis.
• S1P-S1PR3 signaling in adipose and liver tissues plays a protective role against inflammation and steatosis, crucial for maintaining metabolic homeostasis.
• Targeting the S1P-S1PR3 pathway may offer a novel therapeutic strategy for managing metabolic disorders like Type 2 diabetes and obesity.