Effect of MMP-13 inhibition on adipose tissue development
The aim of this study was to determine the effect of matrix metalloprotease 13 (MMP-13) inhibition on adipose tissue development in an in vivo mouse model and in vitro 3T3-L1 cell line model. Excessive caloric intake leads to increased adipose tissue formation via two main processes: adipocyte hypertrophy and hyperplasia. These two processes are supported by several physiological processes that include increased angiogenesis and extracellular matrix remodeling. In this study, we have specifically focused on the remodeling of extracellular matrix. Matrix metalloproteases (MMPs) are enzymes that orchestrate the remodeling process. They help in the relaxation of adipocyte and preadipocyte microenvironment in favor of increased angiogenesis, hyperplasia and hypetrophy. MMP-13 is highly expressed in the late stage of 3T3-L1 adipocyte differentiation. Therefore, we determined the effect of inhibition of MMP-13 during 3T3-L1 differentiation on the expression of differentiation markers. The adipogenic marker, peroxisome proliferator-activated receptor (PPARγ), was markedly suppressed in the inhibitor-treated cells as compared to control cells. Oil red O staining results also indicate reduced lipid storage in the presence of the inhibitor. Knockdown of MMP-13 using small interfering RNA reduced the expression of PPARγ, suggesting that reduction of MMP-13 activity either by pharmacological inhibition or siRNA deletion results in the reduction of adipocyte differentiation. Multiple MMPs are upregulated in obesity, including MMP-2, 9, 13 and 14. Whereas several studies have examined the role of other MMPs in adipose tissue development, there is no systematic study to determine the role of MMP-13 inhibition on adipose tissue development. Therefore, in the first study we examined the effect of MMP-13 inhibition with a novel pharmacological inhibitor, CP-544439, on adipose tissue development in a mouse model of diet-induced obesity. In this study, administration of the inhibitor to mice fed a high fat diet for 6 weeks resulted in reduction of body adiposity. Additionally, the inhibitor improved glucose tolerance. Histological examination of epididymal adipose also showed reduced adipocyte hypetrophy accompanied by increased staining for collagen in the inhibitor treated mice. These results suggest that MMP-13 plays a major role in the degradation of collagen surrounding adipocytes and hypertrophy. Thus its inhibition results in reduced adipocyte size and improved metabolic status of the mice. Taken together, the results presented in this thesis show that inhibition of MMP-13 results in reduced adiposity through direct inhibition of adipocyte differentiation and hypertrophy. Therefore, inhibition of MMP-13 activity may be a strategy to prevent obesity.
Ajuwon, Purdue University.
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