Role of metalloproteinases in adipogenesis and obesity

Obesity has become a major health problem for modern Western-type societies. The worldwide prevalence of obesity has doubled since the 1980’s and today over 600 million adults are obese. Moreover, obesity is associated with the development of chronic diseases such as type 2 diabetes, cardiovascular diseases and fatty liver disease. This presents a heavy burden to the health care sector and has major economical consequences. However, efficient therapies to achieve metabolic health are not readily available. Adipose tissue has played an essential role in the adaptation of humans during evolution, i.e to food scarcity and cold. On the one hand, white adipose tissue is programmed to store excess energy in the form of triglycerides. On the other hand, brown adipose tissue efficiently burns energy to produce heat (thermogenesis). Over the last decade a third type of adipocyte was identified, namely the beige adipocyte. This adipocyte is mainly found in subcutaneous adipose tissue and is bi-functional, meaning that it can adapt to energy storage or to thermogenesis, depending on the metabolic need. A good understanding of adipose tissue biology is necessary for the development of new therapeutic strategies against obesity. Adipose tissue expansion consists of hypertrophy (existing adipocytes increase in volume), hyperplasia (new adipocytes arise from precursor cells), angiogenesis (formation of new blood vessels) and remodeling of the extracellular matrix. The metalloproteinase family is involved in all of these processes. This superfamily can be further divided into several subfamilies including the MMP (matrix metalloproteinases) family. A potential role for MMP-2 and MMP-9 was reported in obesity, although many discrepant results were presented. In the present study, we further investigated the specific roles of MMP-2 and MMP-9 in adipogenesis in vitro. Therefore, we used established in vitro models: - murine embryonic fibroblasts (MEF) derived from wild-type and gene deficient mice were stimulated towards adipogenic differentiation. - 3T3-F442A preadipocytes were differentiated into mature adipocytes, while MMP levels were modulated by genetic knockdown (shRNA-mediated) or overexpression. In agreement with diet studies performed on mice with genetic deficiencies, we demonstrated that MMP-2 but not MMP-9 is an important player in preadipocyte differentiation. Another subfamily of the metalloproteinases is the ADAMTS (A disintegrin and metalloproteinase with thrombospondin type 1 motifs) family. Relatively little is known on the role of this subfamily in adipose tissue development, although it has been reported that several members, including ADAMTS5, are upregulated in adipose tissue of obese mice. We studied the effects of ADAMTS5 on adipogenesis both in vitro and in vivo, and on adipose tissue development in nutritionally-induced obesity in mice. Using 3T3-F442A cells and MEFs, we demonstrated that ADAMTS5 promotes adipogenesis in vitro, and also stimulates de novo adipogenesis in vivo. Moreover, mice with genetic ADAMTS5 deficiency, kept on a high fat diet, developed less visceral adipose tissue mass and were protected against liver steatosis. This hepatic phenotype appears to be due to reduced uptake of triglycerides from the circulation into the liver, thereby protecting liver integrity. It is tempting to speculate that neutralization of ADAMTS5 may protect against diet-induced steatohepatitis. Surprisingly, we also observed an increased mass of brown adipose tissue in ADAMTS5 deficient mice. Moreover, in subcutaneous white adipose tissue of ADAMTS5 deficient as compared to wild-type mice, more beige adipocytes were observed (also known as ‘browning’). The brown adipose tissue was shown to be metabolically active, but only small differences in heat production and energy expenditure were observed, without significant effects of ADAMTS deficiency on total body weight. Furthermore, browning of white adipose tissue was strongly enhanced upon exposure to cold, a known stimulator. These findings indicate that ADAMTS5 plays an important functional role in development of white and brown adipose tissue. It remains to be shown whether neutralization of ADAMTS5 is a viable strategy to enhance thermogenesis and to reduce obesity.status: publishe