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J. Biol. Chem., Vol. 281, Issue 16, 11205-11213, April 21, 2006

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Complex Role of the Vitamin D Receptor and Its Ligand in Adipogenesis in 3T3-L1 Cells^*

From the Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

The vitamin D receptor (VDR) and its ligand 1,25-OH₂-VD₃ (calcitriol) play an essential role in mineral homeostasis in mammals. Interestingly, the VDR is expressed very early in adipogenesis in 3T3-L1 cells, suggesting that the VDR signaling pathway may play a role in adipocyte biology and function. Indeed, it has been known for a number of years that calcitriol is a potent inhibitor of adipogenesis in this model but with no clear mechanism identified. In this study, we have further defined the molecular mechanism by which the unliganded VDR and calcitriol-liganded VDR regulate adipogenesis. In the presence of calcitriol, the VDR blocks adipogenesis by down-regulating both C/EBP mRNA expression and C/EBP nuclear protein levels at a critical stage of differentiation. In addition, calcitriol allows for the up-regulation of the recently described C/EBP corerepressor, ETO, which would further inhibit the action of any remaining C/EBP, whose action is required for adipogenesis. In contrast, in the absence of calcitriol, the unliganded VDR appears necessary for lipid accumulation, since knock-down of the VDR using siRNA both delays and prevents this process. Taken together, these data support the notion that the intracellular concentrations of calcitriol can play an important role in either promoting or inhibiting adipogenesis via the VDR and the transcriptional pathways that it targets. Further examination of this hypothesis in vivo may shed new light on the biology of adipogenesis.

Received for publication, September 20, 2005 , and in revised form, January 12, 2006.

^* This work was supported by grants from Takeda Chemical Industries (Osaka, Japan) (to J. S. F. and A. N. H.) and the National Institutes of Health Grants DKR3728081 (to J. S. F.) and DK056123 (to A. N. H.). 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.

¹ To whom correspondence should be addressed: Division of Endocrinology, Diabetes and Metabolism Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-2151; E-mail: thollenb{at}bidmc.harvard.edu.

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