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Papers In Press, published online ahead of print April 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800206-JLR200

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Journal of Lipid Research, Vol. 50, 602-610, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Sphingosine kinase is induced in mouse 3T3-L1 cells and promotes adipogenesis

Takeshi Hashimoto, Junsuke Igarashi¹ and Hiroaki Kosaka

Department of Cardiovascular Physiology, Kagawa University Faculty of Medicine, Kagawa, Japan 761-0793

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one table and four figures.

This study was supported in part by Grants-in-Aid from the Nankai Ikuei Foundation (to T.H., Kagawa, Japan), from the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to J.I., Tokyo, Japan), and from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T.H., 19790650 and to J.I., 17790151).

Published, JLR Papers in Press, November 19, 2008.

¹ To whom correspondence should be addressed. e-mail: igarashi{at}med.kagawa-u.ac.jp

Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that exerts numerous biological activities both as a receptor ligand and as an intracellular second messenger. In the present study, we explored roles of sphingosine kinase (SphK), an S1P-producing enzyme, in adipose tissue. We utilized mouse 3T3-L1 cells as an in vitro model of adipogenesis, using a mixture of insulin/dexamethasone/3-isobutyl-1-methylxanthine (IBMX) to induce differentiation. Real-time quantitative PCR (qRT-PCR) assays revealed that the expression levels of transcripts encoding both isoforms of SphK-1 and SphK-2 are up-regulated during adipogenesis (37.6- and 6.6-fold vs. basal, P < 0.05, respectively). Concomitantly, SphK-1/SphK-2 protein abundance and S1P contents of these cells increased at 3 days after hormonal stimulation. Loss-of-function approaches by pharmacological inhibition of SphK activity as well as by transfection with small interfering RNA (siRNA) against SphK-1 led to significant attenuation of lipid droplet accumulation and adipocyte marker gene expression. We detected marked elevation of SphK-1 mRNA in adipose tissue derived from 13-week-old ob/ob mice with obese phenotype than their lean littermates. These results suggest that increased expression of SphK, an S1P-producing enzyme, plays a significant role during adipogenesis, potentially providing a novel point of control in adipose tissue.

Supplementary key words sphingosine 1-phosphate • differentiation • adipose tissue

Abbreviations: aP2, adipocyte fatty acid binding protein-2; DHS, DL-threo-dihydrosphingosine; DMS, N,N-dimethylsphingosine; IBMX, 3-isobutyl-1-methylxanthine; OPA o-phthalaldehyde; PPAR, peroxisome proliferator-activated receptor-; qRT-PCR, real-time quantitative RT-PCR; siRNA, small interfering RNA; SphK, sphingosine kinase; S1P, sphingosine 1-phosphate

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