NOTCH-1 CONTROLS THE EXPRESSION OF FATTY ACID-ACTIVATED TRANSCRIPTIONFACTORS AND IS REQUIRED FOR ADIPOGENESIS

Notch, a transmembrane receptor member of the homeotic epidermal growt h factor-like family of proteins, participates in cell-to-cell signali ng to control cell fate during development, Activated Notch-1 construc ts lacking the extracellular region prevent differentiation of several mammalian cells in vitro, This effect, however, bypasses the normal m echanisms of cell-to-cell interactions in which Notch-1 participates, We investigated the role of Notch-1. in the hormone-induced adipocyte differentiation of 3T3-L1 fibroblasts, a paradigmatic model of adipoge nesis that requires cell-to-cell contact, Unlike other differentiation models, Notch-1 expression and function were necessary conditions for adipogenesis, Impaired Notch-1 expression by antisense Notch-1 constr ucts prevented adipocyte differentiation. Strategies aimed at blocking putative Notch/ligand interactions also blocked adipogenesis, implica ting Notch as a critical molecule in cell-to-cell signaling necessary for differentiation, Inhibition of Notch-1 expression or function decr eased the expression of peroxisomal proliferator-activated receptors d elta and gamma, transcription factors that control adipocyte different iation and that are up-regulated at cell confluence, These results imp licate Notch in the commitment of 3T3-L1 cells to undergo adipogenesis by controlling the expression of the principal regulators of this pro cess.