The role of macrophage-derived MMP12 in diet-induced obesity

Background. Macrophages accumulation in adipose tissue of obese mice is accompanied by increased expression of pro-inflammatory adipokines, cytokines and chemokines, leading to the proposal that macrophages are of central importance in the systemic inflammation associated with obesity. Matrix metalloproteinases (MMPs) are implicated in cytokine and chemokine release, matrix remodeling, and the release of inflammatory mediators. Levels of macrophage metalloelastase (MMP-12, a macrophage-specific enzyme) increase dramatically in the stromovascular fraction of adipose tissue when mice are fed a high-fat diet. We used mice deficient in MMP-12 (Mmp12-/- ) to investigate the role of macrophages in diet-induced obesity.

Methods and results. C57BL/6J (WT) and Mmp12 -/- mice were fed a high or low fat diet (Research Diets, with 60% or 12% Kcal fat) for 10 weeks after weaning. Mmp12 -/- mice fed a high-fat diet gained markedly more weight than did WT mice (43.9±0.8 vs 35.2±0.6 g, p<0.01, n≥50/group); they also exhibited significantly more adipose tissue mass (43.0±1.6% vs 24.3±3.0%, p<0.05, n=4/group) and less lean mass (47.6±1.6% vs 63.1±2.4%, p<0.05, n=4/group) than WT mice. Although, diet-induced obese Mmp12-/- mice did not eat more than WT mice, they were less active than WT mice. Surprisingly, despite the increased weight gain, Mmp12-/- mice were not more insulin resistant than WT mice. Furthermore, levels of circulating cytokines (IL-6, MCP-1, Resistin, and tPAI-1) and inflammatory cytokines in adipose tissue (IL-6, MCP-1, and TNF-α) were similar in both diet-induced obese Mmp12-/- and WT mice. However, there were increased macrophages in adipose tissue in diet-induced obese Mmp12-/- mice compared with WT mice. Levels of markers in adipose tissue for alternatively activated macrophages were significantly higher in Mmp12-/- than WT mice.

Conclusion. Our observations indicate that MMP-12 expressed by macrophages plays previously unsuspected roles in adipose tissue accumulation, a shift of adipose tissue macrophage polarization, and systemic inflammation during diet-induced obesity.