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/EBP␣ and peroxisome proliferator-activated receptor ␥ (PPAR␥) induction and could be overcome by retroviral expression of either C/EBP␣ or PPAR␥2. 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.

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

“…It is not unusual for intracellular and extracellular proteins to be necessary for a biological effect, but when expressed in excess to be inhibitory. For example, Hes-1 is necessary for adipogenesis, but its overexpression inhibits adipogenesis, twisted gastrulation and connective tissue growth factor are necessary for BMP effects on osteoblastogenesis, but when in excess they can be inhibitory [48][49][50][51]. Similarly, CHOP is necessary for normal osteoblastic function, but when in excess, and under specific conditions in vivo, it may interact with intracellular proteins necessary for osteoblastic function and become inhibitory.…”

Protein Kinase C Activates Human Lipocalin-type Prostaglandin D Synthase Gene Expression through De-repression of Notch-HES Signaling and Enhancement of AP-2β Function in Brain-derived TE671 Cells

“…Moreover, the ␣-glucosidase gene was shown to be regulated by the Notch-Hes signaling in HepG2 cells (49). Hes-1 regulates differentiation of preadipocytes (50), and acts as a tumor suppressor in epithelial cells and as a mediator of the proliferative effect of 17␤-estradiol on breast cancer cells (51). Thus, the Notch-Hes signal regulates the transcription of not only neuronal genes but also that of non-neuronal genes in a variety of cells.…”

Transcriptional activation of pref-1 by E2F1 in 3T3 L1 cells

“…Hes-1 directly down-regulates E2F1 ex-http://bmbreports.org pression by binding a specific CACGAG-site within the E2F1 promoter (17,18). Notch signaling is essential for adipogenesis in 3T3-L1 cells, promoting differentiation through the downregulation of pref-1 transcription and the activation of Hes-1 expression (19,20). In our study, the levels of E2F1 and pref-1 were decreased during the early differentiation of adipocytes.…”