Inhibition of MMP-13 prevents diet-induced obesity in mice and suppresses adipogenesis in 3T3-L1 preadipocytes

Abstract

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.

Novel Function of Serine Protease HTRA1 in Inhibiting Adipogenic Differentiation of Human Mesenchymal Stem Cells via MAP Kinase-Mediated MMP Upregulation

“…Our previous studies using synovial fibroblasts and intervertebral disc (IVD) cells have identified MMPs to be strongly upregulated in response to HTRA1 stimulation, being mediated through the production of reactive fibronectin species . In addition to their ability to induce HSPG cleavage and shedding , MMPs are also potent regulators of adipogenesis, having both inhibitory and stimulatory effects . This led us to investigate the possibility that MMP production by hMSCs undergoing adipogenesis might be regulated by HTRA1.…”

Effects of matrix metalloproteinases on the fate of mesenchymal stem cells

“…The expression of MMP-9 in this study was upregulated in the first 2 days of stimulation for adipogenic differentiation, followed by a rapid decrease until the end of differentiation, suggesting that the upregulation of MMP-9 does not necessarily have a key role in this process [14]. In another study, treating preadipocytes with a selective inhibitor for MMP-13 or silencing MMP-13 by siRNA resulted in reduced adipogenic differentiation, suggesting the important role of MMP-13 in adipogenesis [15]. …”

Multifaceted Breast Cancer: The Molecular Connection With Obesity

“…Bauters et al (2015), in fact, observed that murine embryonic fibroblasts derived from MMP-2 deficient mice and MMP-2 knockdown 3T3-F442A pre-adipocytes showed significantly impaired differentiation into mature adipocytes with 90% reduction of intracellular lipid content and expression of proadipogenic markers. In the same way, Shih and Ajuwon (2015) showed that MMP-13 knockdown 3T3-L1 cells display reduced differentiation and reduced expression of PPARg.…”