Down-regulation of tissue inhibitor of metalloproteinase-3 (TIMP-3) expression is necessary for adipocyte differentiation.
Matrix metalloproteinase activity is essential for proper extracellular matrix remodeling that takes place during adipose tissue formation. Four tissue inhibitors of matrix metalloproteinases (TIMPs) regulate their activity. However, the role of TIMPs in adipocyte differentiation is poorly understood. We found that the expression of all TIMPs was modified during adipocyte differentiation, but that of TIMP-3 was distinguished by its extreme down-regulation. TIMP-3 expression was closely linked to the differentiation process. Indeed, it remained low during the adipocyte differentiation but increased when cell differentiation was prevented. We identified the transcription factor Sp1 as being responsible for the regulation of TIMP-3 expression during adipocyte differentiation. Overexpression of TIMP-3 reduced adipocyte differentiation, underlining its active role in this process. TIMP-3 overexpression decreased the expression of the early and obligate key inductors of adipogenesis Krüppel-like factor 4 (Klf4), early growth response 2 (Egr2/Krox20), and CAAT/enhancer-binding protein beta (C/EBPbeta). Our results indicate that during preadipocyte differentiation, the Sp1-dependent decrease in TIMP-3 expression is required for the successful implementation of the adipocyte differentiation program.
Bernot
Denis
D
INSERM, U626, Faculté de Médecine, Université de la Méditérranée, 27 Boulevard Jean Moulin, Marseilles 13385 Cedex 5, France.
Barruet
Emilie
E
Poggi
Marjorie
M
Bonardo
Bernadette
B
Alessi
Marie-Christine
MC
Peiretti
Franck
F
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D016329:Sp1 Transcription Factor / Q000502:physiology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*
C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D016329:Sp1 Transcription Factor; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3