Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation.
Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling, a process that takes place during obesity-mediated adipose tissue formation. Here, we examine expression profiles and the potential role of MMPs and their tissue inhibitors (TIMPs) in adipose tissue remodeling during obesity. Expression patterns are studied by Northern blot and real-time PCR in two genetic models of obesity (ob/ob and db/db mice) and in a diet-induced model of obesity (AKR mice). Of the MMPs and TIMPs studied, mRNA levels for MMP-2, MMP-3, MMP-12, MMP-14, MMP-19, and TIMP-1 are strongly induced in obese adipose tissues compared with lean tissues. In contrast, MMP-7 and TIMP-3 mRNAs are markedly decreased in obesity. Interestingly, enzymatic activities of MMP-12 and of a new identified adipocyte-derived 30-kDa metalloproteinase are enhanced in obese adipose tissue fractions, demonstrating that MMP/TIMP balance is shifted toward increased matrix degradation in obesity. Finally, we analyze the modulation of MMP-2, MMP-19, and TIMP-1 during 3T3-L1 preadipocyte differentiation, and we explore the effect of inhibition of MMP activity on in vitro adipogenesis. We find that the synthetic MMP inhibitor BB-94 (Batimastat) decreases adipose conversion of 3T3-L1 and primary rat preadipocytes. BB-94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of CCAAT/enhancer-binding protein beta, a transcription factor that is thought to play a major role in the adipogenic program. Such findings support a role for the MMP/TIMP system in the control of proteolytic events and adipogenesis during obesity-mediated fat mass development.
Chavey
Carine
C
INSERM, Unité 145, Institut Fédératif de Recherche (IFR) 50, 06107 Nice, France.
Mari
Bernard
B
Monthouel
Marie-Noëlle
MN
Bonnafous
Stéphanie
S
Anglard
Patrick
P
Van Obberghen
Emmanuel
E
Tartare-Deckert
Sophie
S
D017667:Adipocytes / Q000166:cytology / Q000201:enzymology*; D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000201:enzymology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology; D004032:Diet; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D053508:Matrix Metalloproteinase 12; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics*; D053504:Matrix Metalloproteinases, Membrane-Associated; D053505:Matrix Metalloproteinases, Secreted; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D000077154:Rosiglitazone; D017154:Stromal Cells / Q000166:cytology / Q000201:enzymology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D013876:Thiophenes / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics
D022782:CCAAT-Enhancer-Binding Protein-beta; D007004:Hypoglycemic Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; D013876:Thiophenes; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D000077154:Rosiglitazone; D010649:Phenylalanine; C080985:batimastat; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D053505:Matrix Metalloproteinases, Secreted; D008666:Metalloendopeptidases; C108362:matrix metalloproteinase 19; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D053508:Matrix Metalloproteinase 12