Down-regulation of Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) Expression Is Necessary for Adipocyte Differentiation

Abstract

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 ␤ (C/EBP␤). 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.Development of obesity is associated with extensive modifications of the composition and architecture of the adipose tissue. These events necessitate dynamic changes of cell-matrix interactions and extracellular matrix remodeling that are made possible by the alteration of pericellular proteolytic activities. Normal turnover of the extracellular matrix is regulated by the opposing activities of proteinases and their inhibitors (1, 2).Matrix metalloproteinases (MMPs) 4 are a family of Ͼ20 secreted zinc-dependent proteinases involved in the extracellular matrix degradation, the release of sequestered growth fac-

Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis

“…RT-qPCR analysis of whole muscle of FAP no PTCH1 and control mice demonstrated that removing PTCH1 from FAPs also up regulates Timp3 expression (Figure S6B). As addition of TIMP3 to 3T3-L1 cells, a commonly used model of adipogenesis, had previously been shown to inhibit adipogenesis in vitro (Bernot et al, 2010), we hypothesized that elevated Timp3 expression by FAPs may underlie the cell non-autonomous suppression of adipogenesis caused by loss of cilia in vivo. Examination of ciliogenesis during 3T3-L1 adipogenesis revealed that nearly all 3T3-L1 cells possessed cilia prior to differentiation, but lost their cilia as they differentiated into adipocytes (Figure S6C), similar to previous reports (Marion et al, 2009; Zhu et al, 2009) and like FAPs in vivo (Figure S2A).…”

“…Timp3 encodes a secreted inhibitor of several MMPs and ADAM proteins, overexpression of which reduces adipogenesis (Bernot et al, 2010; Khokha et al, 2013). Suppressing Timp3 expression blocked the ability of Hh pathway activation to inhibit adipogenesis, providing complementary loss-of-function evidence for the role for TIMP3 in inhibiting adipogenesis.…”

Tissue inhibitor of metalloproteinases-3 transfer suppresses malignant behaviors of colorectal cancer cells

“…TIMP3 is recognized as a multifunctional molecule in cell biology, covering cell differentiation, angiogenesis and immunology. 8,16,17 It has been reported that TIMP3 was involved in cancer apoptosis and invasion. In terms of the status of TIMP3 in cancer, it is also found downregulated in 95.2% clear renal cell carcinoma.…”

Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue

“…Macrophages are not only capable of mediating inflammatory responses, but also aid remodelling processes that may occur to accommodate the expansion of adipose tissue mass upon insulininduced weight gain. However, the expression levels of genes related to adipose tissue remodelling, including those for PAI-1, TIMP-1 (tissue metallopeptidase inhibitor 1), matrix metalloproteinase-2 (MMP-2), MMP-3 and MMP-11 [18][19][20], were not significantly changed. Although weight gain might lead to an upregulation of the genes related to angiogenesis and extracellular matrix remodelling [21], our results suggest that insulin-induced weight gain exerts different effects on extracellular matrix remodelling.…”