Exp Mol Med.  2012 Oct;44(10):603-614.

Antiobesity activity of a sphingosine 1-phosphate analogue FTY720 observed in adipocytes and obese mouse model

• Moon MH
• Jeong JK
• Lee JH
• Park YG
• Lee YJ
• Seol JW
• Park SY

Abstract

Higher levels of body fat are associated with an increased risk for development numerous adverse health conditions. FTY720 is an immune modulator and a synthetic analogue of sphingosine 1-phosphate (S1P), activated S1P receptors and is effective in experimental models of transplantation and autoimmunity. Whereas immune modulation by FTY720 has been extensively studied, other actions of FTY720 are not well understood. Here we describe a novel role of FTY720 in the prevention of obesity, involving the regulation of adipogenesis and lipolysis in vivo and in vitro. Male C57B/6J mice were fed a standard diet or a high fat diet (HFD) without or with FTY720 (0.04 mg/kg, twice a week) for 6 weeks. The HFD induced an accumulation of large adipocytes, down-regulation of phosphorylated AMP-activated protein kinase alpha (p-AMPKalpha) and Akt (p-Akt); down-regulation of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL) and perilipin mRNA as well as up-regulation of phosphorylated HSL (p-HSL, Ser563) and glycogen synthase kinase 3 alpha/beta (p-GSK3alpha/beta). All these effects were blunted by FTY720 treatment, which inhibited adipogenesis and promoted lipolysis. Also, FTY720 significantly decreased lipid accumulation in maturing preadipocytes. FTY720 down-regulated the transcriptional levels of the PPARgamma, C/EBPalpha and adiponectin, which are markers of adipogenic differentiation. FTY720 significantly increased the release of glycerol and the expression of the HSL, ATGL and perilipin, which are regulators of lipolysis. These results show that FTY720 prevented obesity by modulating adipogenesis and lipolysis, and suggest that FTY720 is used for the treatment of obesity.

Keyword

adipocyte; adipogenesis; antiobesity; FTY720; lipolysis

MeSH Terms

3T3-L1 Cells
AMP-Activated Protein Kinases/metabolism
Adipocytes/*drug effects/physiology
Adipogenesis/drug effects
Animals
Anti-Obesity Agents/*pharmacology/therapeutic use
Antigens, Differentiation/genetics/metabolism
Carrier Proteins/genetics/metabolism
Cell Size
Diet, High-Fat/adverse effects
Disease Models, Animal
Enzyme Activation
Gene Expression Regulation, Enzymologic/drug effects
Glycogen Synthase Kinase 3/genetics/metabolism
Lipase/genetics/metabolism
Lipolysis/drug effects
Male
Mice
Mice, Inbred C57BL
Obesity/etiology/metabolism/*prevention & control
Phosphoproteins/genetics/metabolism
Phosphorylation
Propylene Glycols/*pharmacology/therapeutic use
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt/metabolism
Sphingosine/*analogs & derivatives/pharmacology/therapeutic use
Sterol Esterase/metabolism