Dual Roles for the Notch Target Gene Hes-1 in the Differentiation of 3T3-L1 Preadipocytes

Abstract

The process of adipogenesis involves a complex program of gene expression that includes down-regulation of the gene encoding Hes-1, a target of the Notch signaling pathway. To determine if Notch signaling affects adipogenesis, we exposed 3T3-L1 preadipocytes to the Notch ligand Jagged1 and found that differentiation was significantly reduced. This effect could be mimicked by constitutive expression of Hes-1. The block was associated with a complete loss of C/EBPα and peroxisome proliferator-activated receptor γ (PPARγ) induction and could be overcome by retroviral expression of either C/EBPα or PPARγ2. Surprisingly, small interfering RNA (siRNA)-mediated reduction of Hes-1 mRNA in 3T3-L1 cells also inhibited differentiation, suggesting an additional, obligatory role for Hes-1 in adipogenesis. This role may be related to our observation that both Notch signaling and Hes-1 down-regulate transcription of the gene encoding DLK/Pref-1, a protein known to inhibit differentiation of 3T3-L1 cells. The results presented in this study establish a new target downstream of the Notch-Hes-1 pathway and suggest a dual role for Hes-1 in adipocyte development.

We thank Jennifer Schmidt and members of the Kadesch lab for their helpful suggestions.

This work was supported by funds from the NIH (RO1 GM58228 to T.K.) and the American Cancer Society (PF-02-120-01-LIB to D.A.R.). D.A.R. was the recipient of the American Cancer Society-IDEC/Genentech/Ronald Levy postdoctoral fellowship (PF-02-120-01-LIB). P.K.R. was supported through an institutional NIH training grant (T32 CA 09140).