title: Antiobesity activity of a sphingosine 1-phosphate analogue FTY720 observed in adipocytes and obese mouse model.
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.
authors.affiliation: Biosafty Research Institute College of Veterinary Medicine Chonbuk National University Jeonju 561-756, Korea.
authors.forename: Myung Hee
authors.initials: MH
authors.lastname: Moon
authors.forename: Jae Kyo
authors.initials: JK
authors.lastname: Jeong
authors.forename: Ju Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Yang Gyu
authors.initials: YG
authors.lastname: Park
authors.forename: You Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Seol
authors.forename: Sang Youel
authors.initials: SY
authors.lastname: Park
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects* / Q000502:physiology; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D048429:Cell Size; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004789:Enzyme Activation; D000068876:Fingolimod Hydrochloride; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002787:Sterol Esterase / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D055372:AMP-Activated Protein Kinases; D019440:Anti-Obesity Agents; D000943:Antigens, Differentiation; D002352:Carrier Proteins; D000068876:Fingolimod Hydrochloride; D038362:Glycogen Synthase Kinase 3; D008049:Lipase; D000070778:Perilipin-1; D010750:Phosphoproteins; D011409:Propylene Glycols; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine; D002787:Sterol Esterase; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases