Notch-1 controls the expression of fatty acid-activated transcription factors and is required for adipogenesis.
Notch, a transmembrane receptor member of the homeotic epidermal growth factor-like family of proteins, participates in cell-to-cell signaling to control cell fate during development. Activated Notch-1 constructs lacking the extracellular region prevent differentiation of several mammalian cells in vitro. This effect, however, bypasses the normal mechanisms 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 adipogenesis 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 constructs prevented adipocyte differentiation. Strategies aimed at blocking putative Notch/ligand interactions also blocked adipogenesis, implicating Notch as a critical molecule in cell-to-cell signaling necessary for differentiation. Inhibition of Notch-1 expression or function decreased the expression of peroxisomal proliferator-activated receptors delta and gamma, transcription factors that control adipocyte differentiation and that are up-regulated at cell confluence. These results implicate Notch in the commitment of 3T3-L1 cells to undergo adipogenesis by controlling the expression of the principal regulators of this process.
Garcés
C
C
Laboratory of Immunobiology, Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Bethesda, Maryland 20852, USA.
Ruiz-Hidalgo
M J
MJ
Font de Mora
J
J
Park
C
C
Miele
L
L
Goldstein
J
J
Bonvini
E
E
Porrás
A
A
Laborda
J
J
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000273:Adipose Tissue / Q000166:cytology / Q000254:growth & development*; D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation; D005227:Fatty Acids / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism; D014162:Transfection
D005227:Fatty Acids; D007328:Insulin; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D016376:Oligonucleotides, Antisense; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors