It is estimated that somewhere between 34 and 61 million people in the US are obese. Likewise in much of the developing world obesity represents a growing problem. Consequently the world obesity market has been predicted to reach $3.7 billion by 2008 sparking a drive to prioritize the identification of novel anti-obesity products. The number of anti-obesity candidates in development has risen 3-fold over the past 7 years and a large number of pharmacological targets are currently under evaluation to boost this activity still further. Ghrelin rerpresents one particularly promising recent target even more recent are the Matrix metalloproteinases (MMPs).

MMPs are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. This family which includes well over 20 metalloproteinases and endogenous inhibitors of the MMPs has been implicated in inflammatory diseases such chronic obstructive airway diseases, atherosclerosis, bone degenerative conditions including rheumatoid arthritis and osteoporosis, wound repair and, perhaps most well known, cancer. MMPs are dramatically up-regulated in malignant tissues and play a role in both metastasis and angiogenesis. Consequently over 20 MMP modulating agents are in pharmaceutical develop, almost half of which are indicated for cancer.

The development of obesity is associated with coordinated cellular processes including adipocyte hypertrophy followed by recruitment of adipocyte precursors, and new fat cell differentiation. These processes as well as accompanying neovascularization are dependent on extensive extracellular matrix reorganization suggesting that MMPs may play a role in obesity. Recent data has suggested that mature fat cells and cultured adipocytes secrete MMP-2 and MMP-9, and that their proteolytic activities are induced during adipocyte differentiation. Further, elevated expression of MMP-2 has been reported in adipose tissue of obese mice. On the other hand blocking MMP activity decreased differentiation, suggesting that MMP activities were required for adipocyte conversion. In contrast, another study showed that addition of TIMP-1 or the MMP inhibitor GM6001 accelerated 3T3-L1 adipocyte differentiation. It therefore appears clear that MMPs represent an exciting new target for the treatment of obesity, however given the large number of known MMP isoforms, a clear understanding of expression profiles and the potential role of the different MMPs and TIMPs in adipose tissue remodeling during obesity is required. To address this issue INSERM/IGBMC researchers have expressed MMP/TIMP expression patterns in ob/ob and db/db mice and also 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 to lean tissues. In contrast, MMP-7 and TIMP-3 mRNAs are markedly decreased in obesity. When enzyme activity was investigated, activity of MMP-12 and a newly identified adipocyte-derived 30-kDa metalloproteinase was enhanced in obese adipose tissue fractions. This group also observed that the synthetic MMP inhibitor BB-94 (Batimastat) decreases adipose conversion of 3T3-L1 and primary rat preadipocytes and this may reflect an inhibition of MMP19 or MMP2, since expression of these enzymes was regulated during differentiation.

These data offer further proof of concept for targeting the MMP machinery in order to control obesity and allow better subtype targeting. To date few companies have reported the development of MMP inhibitors for the treatment of obesity and further investigation of this field therefore promises the advance of an important aspect of MMP-related therapeutics.

Entry date February, 2003

Adapted from Chavey et al, J Biol Chem 2003 Jan 15; [epub ahead of print] - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk