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

Sang-Youel Park,You-Jin Lee,Jae-Won Seol,Myung-Hee Moon,Jae-Kyo Jeong,Ju-Hee Lee,Yang-Gyu Park

doi:10.3858/emm.2012.44.10.069

Sang-Youel Park, You-Jin Lee + Show 5 more

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https://doi.org/10.3858/emm.2012.44.10.069

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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 α (p-AMPKα) 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 α/β (p-GSK3α/β). 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 PPARγ, C/EBPα 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.

Highlights

An imbalance between energy intake and expenditure can result in excess triacylglycerol accumulation in adipose tissue, resulting in obesity (Duncan et al, 2007)
The data presented here show for the first time that FTY720 acts as an anti-obesity drug, which induces resistance to high fat diet (HFD)-induced obesity and that the action of FTY720 is mediated by both anti-adipogenic differentiation and pro-lipolytic action
Excessive adipose tissue accumulation is a result of an increase in both adipocyte number that occurs through adipocyte differentiation and adipocyte size that occurs when triacylglycerol synthesis exceeds breakdown

Summary

Introduction

An imbalance between energy intake and expenditure can result in excess triacylglycerol accumulation in adipose tissue, resulting in obesity (Duncan et al, 2007). Obesity is largely attributed to adipocyte hypertrophy that occurs when triacylglycerol synthesis exceeds breakdown (lipolysis), resulting in elevated triacylglycerol storage (Duncan et al, 2007; Jaworski et al, 2007). Unlike triacylglycerol synthesis (Dircks and Sul, 1999; Jaworski et al, 2009) that occurs at high levels in other tissues, lipolysis for the liberation of fatty acids that can be used as an energy source by other tissues is unique to adipocytes (Duncan et al, 2007). Lipolysis and hyperplasia of adipocytes might be important factors in the development of obesity.

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