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J. Biol. Chem., Vol. 279, Issue 39, 40946-40953, September 24, 2004

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EPAS1 Promotes Adipose Differentiation in 3T3-L1 Cells^*

Shigeki Shimba, Taira Wada, Shuntaro Hara, and Masakatsu Tezuka¶

From the Department of Health Science, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan and the Department of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan

Adipose differentiation is regulated by several transcription factors, such as the CAAT/enhancer-binding protein family and peroxisome proliferator activator (PPAR) 2. Several recent studies have shown that the basic helix-loop-helix-PAS superfamily is also involved in the regulation of adipose differentiation. In this study, we investigated the roles played by EPAS1 (endothelial PAS domain protein 1) in adipogenesis. EPAS1, also referred to as hypoxia-inducible factor 2, is a transcription factor known to play essential roles in catecholamine homeostasis, vascular remodeling, and the maintenance of reactive oxygen species, and so forth. During adipose differentiation in 3T3-L1 cells, the level of EPAS1 mRNA began to increase 6 days after the induction, and EPAS1 was highly expressed in differentiated cells. To examine whether EPAS1 is involved in adipogenesis, we first isolated stable clones from 3T3-L1 cells in which we could induce the expression of an EPAS1 C-terminal deletion mutant (designated EPAS1-(1–485)) with the insect hormone. The induction of EPAS1-(1–485) allowed the cells to accumulate only minimum amounts of intracellular lipid droplets. Consistent with the morphological observations, a minimum amount of aP2 and PPAR2 mRNA was induced in the EPAS1-(1–485) cells. We then examined whether or not EPAS1 was able to promote adipogenesis in NIH 3T3 cells, a relatively nonadipogenic cell line. Overexpression of EPAS1 in NIH 3T3 cells induced a significant amount of lipid accumulation compared with that of the control cells in the presence of the PPAR ligand. The results were also confirmed by measuring the expression of adipocyte-related genes. Adenovirus-mediated EPAS1-(1–485) expression resulted in the reduction of basal and insulin-dependent glucose transport in 3T3-L1 adipocytes. The mechanism involved the transcriptional regulation of GLUT1, GLUT4, and IRS3 expression by EPAS1. Taken together, these results suggest that EPAS1 plays several supporting roles in maintaining specific aspects of adipogenesis and adipocyte function including regulation of glucose uptake followed by lipid synthesis.

Received for publication, January 26, 2004 , and in revised form, June 16, 2004.

^* This work was supported in part by a grant from the Ministry of Education, Sciences, Sports, and Culture of Japan (to S. S. and M. T.); a General Individual Research Grant from Nihon University (to S. S.); a grant from the Ministry of Education, Culture, Sports, Science, and Technology to promote multidisciplinary research projects; and an Interdisciplinary General Joint Research Grant from Nihon University (to M. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 81-47-465-5694; Fax: 81-47-465-5637; E-mail: tezukam{at}pha.nihon-u.ac.jp.

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