Adipose tissue remodeling by the matrix metalloproteases (MMPs) is critical for tissue hypertrophy and obesity. MMP-13 is an important protein that is highly expressed in adipose tissue but whose potential role in adipose tissue expansion is poorly characterized. We investigated the effect of pharmacological inhibition of MMP-13 with a selective inhibitor, CP-544439, on adipose tissue mass in mice on a high fat diet, and determined the effect of the inhibitor during in vitro adipocyte differentiation of 3T3-L1 cells. CP-544439 was administered for 6 weeks to mice on a high fat diet. Body adiposity and glucose tolerance was determined. Differentiating 3T3-L1 adipocytes were also treated with the inhibitor for a maximum of 8 days and adipogenesis assessed. Treatment of mice with the inhibitor resulted in reduction in body adiposity and improvement in glucose clearance. Histological examination of epididymal adipose showed reduced adipocyte hypertrophy accompanied by increased staining for collagen in the inhibitor treated mice. Treatment of differentiating 3T3-L1 cells with the inhibitor resulted in reduced adipocyte differentiation. Knockdown of MMP-13 using small interfering RNA in differentiating 3T3-L1 cells reduced adipocyte differentiation indicated by reduced expression of PPARγ. These results suggest that MMP-13 may play a major role in adipose development and its inhibition could be a potential strategy to prevent obesity.

Adipocyte hypertrophy and hyperplasia are supported by several physiological processes including extracellular matrix remodeling. MMPs are enzymes that orchestrate the remodeling process. MMPs regulate the relaxation of adipocyte and preadipocyte microenvironment in favor of hyperplasia and hypetrophy. We determined the effect of matrix metalloprotease 13 (MMP‐13) inhibition on adipose tissue development. In the first study we examined the effect of MMP‐13 inhibition with a MMP‐13 inhibitor, CP‐544439, on mouse adipose tissue development. Administration of CP‐544439, a selective MMP‐13 inhibitor, to mice on high fat diet resulted in reduction of body adiposity. Histology of epididymal adipose tissue showed reduced adipocyte hypertrophy and increased collagen staining by CP‐544439. In 3T3‐L1 adipocytes, PPARγwas markedly suppressed in inhibitor‐treated cells compared to control. Knockdown of MMP‐13 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. Therefore, inhibition of MMP‐13 activity may be a strategy to prevent obesity.