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A Human 3D Extracellular Matrix-Adipocyte Culture Model for Studying Matrix-Cell Metabolic Crosstalk
Published on: November 7, 2019
Effect of matrix metalloproteinase inhibition on adipose tissue development
Diego Demeulemeester1, Désiré Collen, H Roger Lijnen
1Center for Molecular and Vascular Biology, University of Leuven, Belgium.
Abstract:
The effect of Ro 28-2653, a synthetic matrix metalloproteinase (MMP) inhibitor, on adipose tissue development was studied in mice kept on a high fat diet (HFD). Five-week-old male wild-type (C57Bl/6J) mice were fed the HFD (42% kcal as fat, 20.1 kJ/g) and received daily p.o. instillations of inhibitor (30 mg/kg) or vehicle. After 15 weeks of the HFD, the body weight gain was lower in the inhibitor-treated group (7.4 +/- 0.88 g versus 10 +/- 1.4 g) whereas the weights of the isolated subcutaneous (SC) or gonadal (GON) fat deposits were 10-15% lower. The number of adipocytes in adipose tissues of the inhibitor-treated mice was somewhat higher (10-17%) but their diameter was smaller (about 10%). In situ zymography showed reduced gelatinolytic activity in SC (about 2.7-fold) and GON (1.4-fold) adipose tissue of inhibitor-treated mice, whereas their fibrillar collagen content was higher (1.5- and 4.7-fold, respectively). In both SC and GON adipose tissues of inhibitor-treated mice, MMP-2 (gelatinase A) and MMP-14 (membrane type-1 MMP) were 2- to 3-fold upregulated, whereas MMP-9 (gelatinase B) mRNA levels were not affected. Thus, in this in vivo model partial inhibition of gelatinolytic activity is associated with moderate effects on adipose tissue development and cellularity. Possibly, enhanced MMP expression to some extent counteracts the in vivo effect of the inhibitor in adipose tissue.
Insights
A matrix metalloproteinase (MMP) inhibitor, Ro 28-2653, moderately affected adipose tissue development in mice on a high-fat diet. This led to reduced body weight gain and fat mass, with altered adipocyte size and number.
Area of Science:
- Biochemistry
- Physiology
- Pharmacology
Background:
- Matrix metalloproteinases (MMPs) play roles in tissue remodeling, including adipose tissue development.
- Obesity, often exacerbated by high-fat diets (HFD), involves complex changes in adipose tissue.
- Understanding the impact of MMP inhibition on adipose tissue is crucial for metabolic research.
Purpose of the Study:
- To investigate the effects of a synthetic MMP inhibitor, Ro 28-2653, on adipose tissue development in mice fed a HFD.
- To assess the impact of MMP inhibition on body weight, fat deposition, adipocyte characteristics, and extracellular matrix composition.
Main Methods:
- Male C57Bl/6J mice were fed a HFD and treated daily with Ro 28-2653 (30 mg/kg) or vehicle for 15 weeks.
- Body weight, adipose tissue weights (subcutaneous and gonadal), adipocyte number and diameter were measured.
- In situ zymography, collagen content analysis, and gene expression (mRNA) for MMPs were performed.
Main Results:
- Ro 28-2653 treatment resulted in lower body weight gain and reduced weights of subcutaneous and gonadal fat depots.
- Adipose tissue showed a higher number of smaller adipocytes in inhibitor-treated mice.
- Gelatinolytic activity was reduced, collagen content increased, and MMP-2 and MMP-14 were upregulated, while MMP-9 was unaffected.
Conclusions:
- Partial inhibition of gelatinolytic activity by Ro 28-2653 has moderate effects on adipose tissue development and cellularity in vivo.
- Upregulation of MMP expression may partially counteract the inhibitory effects of Ro 28-2653 in adipose tissue.
- Further research is needed to elucidate the precise role of specific MMPs in diet-induced obesity.
