Metalloproteases and Adipogenesis: A Weighty Subject

Abstract

Obesity has become a prevalent health hazard in industrialized countries and is closely associated with a number of pathological disorders such as cancer, cardiovascular disease, hypertension, and non-insulin-dependent diabetes. 1 Even with such serious health implications there is still a great deal to learn before we can fully understand the mechanisms controlling adipocyte differentiation during normal development as well as in pathological conditions. Adipose tissues are aggregates of specially differentiated mesenchymal cells capable of storing large amounts of triglycerides in periods of energy excess and subsequently releasing those triglycerides during energy deprivation. Kawaguchi and colleagues 2 in this issue of The American Journal of Pathology introduce a mouse model that, together with several other recent studies, 3,4 may lead to greater understanding of the events in the extracellular microenvironment that mediate mesenchymal fate decisions and adipocyte differentiation.The adipose lineage arises from a multipotent stem cell of mesenchymal origin from which muscle, bone, and cartilage cells are also derived, although the exact combination of regulatory genes that determine adipocyte fate in development is yet to be determined. 5 In most species, white adipose tissue formation begins before birth and expands rapidly after birth as a result of increased fat cell size as well as an increase in fat cell number. It is not clear whether the increased adipose tissue mass of obesity is because of increases in adipocyte size or number, or a combination thereof. 6 The availability of established preadipocyte cell lines, such as 3T3-L1 and 3T3-F442A, has made it possible to investigate the adipocyte differentiation program under controlled conditions. Through in vitro studies the transcriptional mechanisms that control the transition from the undifferentiated, fibroblast-like preadipocyte into mature, round fat cells are now well understood, particularly with respect to the identification of key transcription factors such as those of the C/EBP and PPAR families. 5,7 Although most studies have been devoted to the hormonal and transcriptional regulation of adipocyte differentiation, new attention is being given to the role of extracellular matrix (ECM) organization in adipogenesis.During adipogenesis ECM remodeling defines the onset of the differentiation process; this is characterized by the conversion from the fibronectin-rich stromal matrix of the preadipocyte to the basement membrane of an adipocyte ( Figure 1). 3,8,9 The expression of ECM components is highly regulated during the process of adipocyte differentiation: types I and III collagen, fibronectin, and ␤1-integrins are down-regulated, whereas type IV collagen and entactin are up-regulated. 5 This ECM remodeling is a key event in the adipogenesis program. Growth of preadipocytes on a fibronectin matrix inhibits adipocyte differentiation, and this effect is overcome by the addition of cytochalasin D, which disrupts actin filaments and promotes roundi...

Paracrine Regulation of Angiogenesis and Adipocyte Differentiation During In Vivo Adipogenesis

“…55 Remodeling of extracellular matrix organization is important for both angiogenesis 17 and adipogenesis. 60 Expression of metalloproteinases such as MMP 2 and MMP 9 is increased during adipocyte differentiation 61 and both endogenous and exogenous metalloproteases induce adipogenesis. 61,62 Of particular interest, MMP-9 has been shown to increase the availability of matrix-bound VEGF in the tissue.…”

Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI

“…In adipose tissue, it is particularly crucial for maintaining structural integrity of adipocytes and plays a critical role in adipogenesis. There are specific sequential alterations in the extracellular milieu during adipocyte differentiation, with a cascade of activation and deactivation of various MMPs, complementing the creation and destruction of the collagen network (31,33). Treatment of 3T3-L1 preadipocytes with a broad-specificity MMP inhibitor hinders the formation of fully differentiated lipid-laden adipocytes (11,16).…”

Factor XIII-A transglutaminase acts as a switch between preadipocyte proliferation and differentiation

“…Whereas preadipocytes themselves regulate synthesis and degradation of collagen and laminin matrices, 69 the pFN matrix accumulation appears to be regulated by the presence of FXIII-A in the cells. For personal use only.…”