Macrophage elastase (MMP-12) in expanding murine adipose tissue.

BACKGROUND: Matrix metalloproteinases (MMPs) are known to play a role in adipose tissue development, but little information is available on the role of individual proteinases. Expansion of adipose tissue is associated with an increased macrophage content. Macrophage elastase (MMP-12) has an important role in macrophage infiltration, which induces pro-inflammatory effects in adipose tissue. METHODS: The role of MMP-12 was investigated in adipose tissues of MMP-12 deficient and wild-type control mice kept on normal chow or on high fat diet for 15 weeks. RESULTS: MMP-12 deficiency had no significant effect on total body weight or on subcutaneous (SC) or gonadal (GON) adipose tissue mass. Adipocyte and blood vessel size and density in SC and GON adipose tissues of obese mice were also comparable in MMP-12 deficient and control mice. Macrophage infiltration in SC and GON adipose tissues was not affected by MMP-12 deficiency, but the amount of crown-like structures (CLS) was significantly lower. MMP-12 deficiency did not affect elastin content in the extracellular matrix of SC or GON adipose tissue. CONCLUSIONS: Adipose tissue mass and composition in mice with nutritionally induced obesity was not markedly affected by MMP-12 deficiency, except for an apparently lower degree of CLS. GENERAL SIGNIFICANCE: MMP-12 does not seem to be essential for macrophage infiltration in adipose tissue, but contributes to the formation of CLS surrounding moribund adipocytes.

Effect of gelatinase inhibition on adipogenesis and adipose tissue development.

1. The potential of the matrix metalloproteinase (MMP) inhibitor ABT-518 to affect pre-adipocyte differentiation in vitro and adipose tissue development in vivo was investigated using mouse models of adipogenesis and obesity. 2. Differentiation of 3T3-F442A pre-adipocytes into mature adipocytes was enhanced in a dose-dependent manner by the addition of ABT-518 (0-100 µmol/L). This was associated with increased expression of the adipogenic markers adipocyte fatty acid-binding protein 2 (AP2), peroxisome proliferator-activated receptor γ and adiponectin. 3. Feeding 5-week-old male wild-type mice with a high-fat diet, with or without ABT-518 (to achieve a dose of 100 mg/kg per day), for 16 weeks resulted in a significant reduction in bodyweight throughout the experimental period. Magnetic resonance spectroscopy revealed that the lipid : water ratio was significantly lower in ABT-518-treated mice. The total weight of isolated subcutaneous or gonadal fat depots did not differ significantly following ABT-518 treatment, but adipocyte and blood vessel size were significantly reduced in the gonadal fat. 4. Administration of ABT-518-2 (100 mg/kg per day for 10 weeks) to 5-week-old male wild-type mice with established obesity maintained on a high-fat diet had no effect on total bodyweight at the end of the experiment, but was associated with reduced blood vessel size in the fat depots. 5. Thus, the MMP inhibitor ABT-518 stimulates differentiation of 3T3-F442A pre-adipocytes in vitro. It mildly reduces bodyweight gain in a murine model of diet-induced obesity, but does not affect established obesity.

A functional role of gelatinase A in the development of nutritionally induced obesity in mice.

BACKGROUND: Development of adipose tissue is a complex process involving adipogenesis, angiogenesis and proteolytic remodeling of the extracellular matrix. The matrix metalloproteinase (MMP) system plays an important role in these processes. OBJECTIVE: To establish a functional role of gelatinase A (MMP-2) in the development of adipose tissue. METHODS: Mice with genetic deficiency in gelatinase A (MMP-2(-/-)) and their wild-type littermates (MMP-2(+/+)), as well as wild-type mice treated with a gelatinase inhibitor, were kept on a high-fat diet (HFD) for 15 weeks, and this was followed by analysis of weight and composition of the fat pads. RESULTS: MMP-2(-/-) mice gained significantly (P < 0.05) less weight on the HFD than MMP-2(+/+) mice, resulting in lower body weights (P < 0.0005). The weights of the isolated subcutaneous and gonadal adipose tissues were also significantly lower (P < 0.005 and P < 0.0005, respectively). Immunohistochemical analysis revealed significant (P < 0.05) adipocyte hypotrophy in both fat pads. Treatment of wild-type mice with the gelatinase inhibitor Tolylsam resulted in an approximately 15% reduction of body weight (P < 0.0001) and significantly lower subcutaneous and gonadal adipose tissue mass, associated with adipose hypotrophy (all P < 0.0001). CONCLUSION: Deficiency of MMP-2 impairs adipose tissue development in mice by contributing to adipocyte hypotrophy.