Adipocyte hypertrophy in stromelysin-3 deficient mice with nutritionally induced obesity

Center for Molecular and Vascular Biology, University of Leuven, Belgium.
Thrombosis and Haemostasis (Impact Factor: 4.98). 04/2002; 87(3):530-5.
Source: PubMed


Several matrix metalloproteinases (MMPs), including the stromelysins MMP-3 and MMP-11, are expressed in adipose tissue. To investigate a potential role of MMP-11 (stromelysin-3) in adipose tissue development, five-week-old male wild-type mice (MMP-11+/+) or mice with deficiency of MMP-11 (MMP-11-/-) were fed a high fat diet (HFD, 42% fat) for 15 weeks. Haematologic parameters, including white and red blood cells, platelets, haemoglobin and haematocrit, and metabolic parameters including glucose, triglycerides and total cholesterol were not different for both genotypes. At the time of sacrifice, the body weight of the MMP-11-/- mice was higher than that of the MMP-11+/+ mice (36+/-1.4 g versus 29+/-0.9 g, p = 0.0002). The weight of the isolated subcutaneous (SC) and gonadal (GON) fat deposits was also higher in MMP-11-/- mice (620+/-150 mg versus 280+/-28 mg for SC fat, and 970+/-180 mg versus 430+/-62 mg, p < 0.05, for GON fat). Adipocytes in MMP-11-/- adipose tissue were hypertrophic as compared to MMP-11+/+ adipocytes (volume of 57+/-12 x 10(3) microm3 versus 31+/-2.4 x 10(3) microm3 for SC fat, and 100+/-18 x 10(3) microm3 versus 57+/-7.6 x 10(3) microm3 for GON fat; both p < 0.06). In nutritionally induced obesity models in mice a potential role of the fibrinolytic system was suggested in adipocyte hypertrophy. The hypertrophy observed in this model is, however, not related to changes in fibrinolytic parameters, as suggested by our finding that levels of t-PA, u-PA and PAI-1 antigen as well as t-PA and u-PA activity were not different in SC or GON adipose tissue extracts of both genotypes. As the main biological function of MMP-11 remains unknown, it is not clear whether the adipocyte hypertrophy in MMP-11-/- adipose tissue is directly related to the deficiency or to other pathways affected by MMP-11.

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    • "Despite many studies on the MMPs, their individual (patho)physiological functions in AT remain largely unknown. Single gene deficiency of Mmp9 (92 kDa-gelatinase B), Mmp10 or Mmp12 in mice had no apparent effect on adiposity [6] [7] [8], whereas deficiency of Mmp3, Mmp11 or Mmp19 in mice kept on a high fat diet led to enhanced development of AT [9] [10] [11]. In contrast, Mmp14 or Mmp2 (72 kDa-gelatinase A) deficiency resulted in impaired murine AT development [12] [13]. "
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    ABSTRACT: Expansion of adipose tissue is dependent on adipogenesis, angiogenesis and extracellular matrix remodeling. A functional role in these processes was suggested for the gelatinase subfamily of the matrix metalloproteinases. Here, we have evaluated a potential role of gelatinase A (MMP-2) in adipogenesis. Murine embryonic fibroblasts (MEF) were derived from wild-type or MMP-2 deficient mice. Genetic manipulation of Mmp2 (shRNA-knockdown or overexpression) was performed in 3T3-F442A preadipocytes. Cell cultures were subjected to an adipogenic medium. As an in vivo model for de novo adipogenesis, 3T3-F442A preadipocytes with or without knockdown were injected subcutaneously in Nude BALB/c mice kept on high fat diet. Mmp2 deficient MEF, as compared to controls, showed significantly impaired differentiation into mature adipocytes, as demonstrated by 90% reduced intracellular lipid content and reduced expression of pro-adipogenic markers. Moreover, selective Mmp2 knockdown in 3T3-F442A preadipocytes resulted in significantly reduced differentiation. In contrast, overexpression of Mmp2 resulted in markedly enhanced differentiation. In de novo formed fat pads resulting from preadipocytes with Mmp2 knockdown expression of aP2, Ppar-γ and adiponectin was significantly lower, and collagen was more preserved. The fat pad weights as well as size and density of adipocytes or blood vessels were, however, not significantly different from controls. Our data directly support a functional role of MMP-2 in adipogenesis in vitro, and suggest a potential role in in vivo adipogenesis. Selective modulation of MMP-2 levels affects adipogenesis. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Apr 2015 · Biochimica et Biophysica Acta
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    • "Inactivation of MMP3 on a high-fat diet results in increased development of adipose tissue with a hyperplastic as well as a hypertrophic response [31]. Similar observations were made after inactivation of MMP9 and MMP11 [24, 32]. Contrasting observations have been made with pharmacological inhibition of MMPs in mice on a high-fat diet. "
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    ABSTRACT: The central role of the adipose tissue in lipid metabolism places specific demands on the cell structure of adipocytes. The protein composition and dynamics of the extracellular matrix (ECM) is of crucial importance for the functioning of those cells. Adipogenesis is a bi-phasic process in which the ECM develops from a fibrillar to a laminar structure as cells move from the commitment phase to the growth phase characterized by storage of vast amounts of triglycerides. Mature adipocytes appear to spend a lot of energy on the maintenance of the ECM. ECM remodeling is mediated by a balanced complement of constructive and destructive enzymes together with their enhancers and inhibitors. ECM remodeling is an energy costing process regulated by insulin, by the energy metabolism, and by mechanical forces. In the obese, overgrowth of adipocytes may lead to instability of the ECM, possibly mediated by hypoxia.
    Full-text · Article · Apr 2010 · Cellular and Molecular Life Sciences CMLS
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    • "MMP3 (or stromelysin 1) has been found to activate MMP1 and impair adipose tissue development [30] [31]. Low levels of stromelysins (such as MMP3 and MMP10) have been linked to obesity [30] [32]. MMP10 degrades extracellular matrix thereby negatively regulates angiogenesis and vascular remodeling [33]. "

    Full-text · Chapter · Mar 2010
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