Author:

Keywords:

Gelatinases, Adipose Tissue, MMP, Obesity

Abstract:

In 1999 the World Health Organization (WHO) declared obesity a worldwide epidemic. Today, it is estimated that around 500 million people worldwide are obese, and more than 1.6 billion are overweight. Diseases associated with excess body weight include among others: cardiovascular disease, hypertension, stroke, diabetes type II, atherosclerosis and certain forms of cancer. As a result, obesity recently became the number one cause of preventable death.Obesity is defined as an excessively high amount of adipose tissue in relation to lean body mass. Development of adipose tissue is a complex process in which several growth factors, cytokines, hormones and proteinases contribute to adipogenesis (formation of adipocytes), angiogenesis (formation of blood vessels) and proteolytic remodeling of the extracellular matrix (ECM). The matrix metalloproteinases (MMPs) form a family of zinc-dependent endopeptidases that play an important role in these processes by degradation of ECM and basement membrane components, by altering cell interactions and/or by activation of latent growth factors. This has led to the hypothesis that modulation of the activity of certain MMPs may have an effect on adipose tissue development. In the present study we have focused on the contribution of MMP-2 (gelatinase A) and MMP-9 (gelatinase B). It was previously shown that they are both expressed by adipocytes and modulated during development of adipose tissue. To evaluate their potential role in adipogenesis, we set up a range of in vivo and in vitro experiments using different murine models.In vivo:- MMP-2 and MMP-9 deficient mice were kept on a high fat diet (HFD) for 15 weeks and compared to wild-type littermates. This revealed no differences for the MMP-9-deficient mice. Incontrast, MMP-2 deficient mice had a 20% reduction of body weight, associated with smaller fat pads en hypotrophy of adipocytes and preservation of collagen.- Wild-type mice on a HFD treated with a relative gelatinase specific inhibitor (Tolylsam) for 15 weeks, developed less adipose tissue, resulting in lower body weights. This was associated with adipocyte hypotrophy and reduced vascularization and higher levels of total collagen. - Leptin deficient ob/ob mice (a genetically induced obesity model) were significantly leaner when treated with Tolylsam.- Adipose tissue growth was impaired in wild obese type mice that were switched to a HFD supplemented with Tolylsam, whereas mice that were kept on the HFD only, continued to gain weight. Tolylsam treatment resulted in preservation of collagen. - De novo fat pad formation in NUDE mice following injection of 3T3-F442A preadipocytes was impaired in mice treated with Tolylsam. - MMP-2 deficient mice developed less adipose tissue when treated with Tolylsam. This was associated with adipocyte hypotrophy and reduced angiogenesis. In vitro:- Downregulation of MMP-2 expression in 3T3-F442A preadipocytes resulted in reduced differentiation into mature adipocytes. - 3T3-F442A preadipocytes cultured in the presence of Tolylsam showed increased differentiation as compared to vehicle treated cells. This may be related to the relatively low substrate specificity of Tolylsam.Taken together, these results reveal divergent functions for gelatinases in the development of adipose tissue: MMP-2 appears to enhance adipose tissue development in mice on high fat diet, at least in part by contributing to adipocyte growth, whereas MMP-9 does not seem crucial. In addition, adipose tissue development can be impaired by oral administration of the relatively gelatinase-specific inhibitor Tolylsam, which is not only a MMP inhibitor, preserving collagen in the ECM, but also impairs blood vessel formation.