Matrix Metalloproteinases Are Differentially Expressed in Adipose Tissue during Obesity and Modulate Adipocyte Differentiation

Carine Chavey,Bernard Mari,Marie-Noëlle Monthouel,Stéphanie Bonnafous,Patrick Anglard,Emmanuel Van Obberghen,Sophie Tartare-Deckert

doi:10.1074/jbc.m209196200

Abstract

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.

Highlights

Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling, a process that takes place during obesity-mediated adipose tissue formation
Northern blot analysis showed that MMP-2, MMP-3, MMP-12, MMP14, and MMP-19 mRNA levels were markedly increased in adipose tissue of both ob/ob and db/db mice compared with their lean littermates (C57BL/6) (Fig. 1A)
We propose that the MMP/tissue inhibitors of MMPs (TIMPs) system might play an integral role in obesity-mediated adipose tissue growth

Summary

Introduction

Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling, a process that takes place during obesity-mediated adipose tissue formation. BB-94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of CCAAT/enhancer-binding protein ␤, 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. In a course of differential gene expression analysis between lean and obese adipose tissues, we recently identified osteonectin/ SPARC, a protein involved in dynamic interactions between cell and matrix, up-regulated in obesity [5]. MMPs participate in many physiological and pathological processes such as embryonic development, angiogenesis, wound repair, reproductive cycling, and metastasis [6, 7] In addition to their direct influence on the degradation of structural matrix molecules, MMPs have been implicated in the generation of bioactive molecules.

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