Matrix metalloproteinase 11 protects from diabesity and promotes metabolic switch.

Nassim Dali-Youcef,Sébastien Blaise,Catherine Postic,Marie-Christine Rio,Philippe Valet,Karim Hnia,Stéphane Blanc,Catherine Tomasetto,Nadia Messaddeq

doi:10.1038/srep25140

Abstract

MMP11 overexpression is a bad prognostic factor in various human carcinomas. Interestingly, this proteinase is not expressed in malignant cells themselves but is secreted by adjacent non-malignant mesenchymal/stromal cells, such as cancer associated fibroblasts (CAFs) and adipocytes (CAAs), which favors cancer cell survival and progression. As MMP11 negatively regulates adipogenesis in vitro, we hypothesized that it may play a role in whole body metabolism and energy homeostasis. We used an in vivo gain- (Mmp11-Tg mice) and loss- (Mmp11−/− mice) of-function approach to address the systemic function of MMP11. Strikingly, MMP11 overexpression protects against type 2 diabetes while Mmp11−/− mice exhibit hallmarks of metabolic syndrome. Moreover, Mmp11-Tg mice were protected from diet-induced obesity and display mitochondrial dysfunction, due to oxidative stress, and metabolic switch from oxidative phosphorylation to aerobic glycolysis. This Warburg-like effect observed in adipose tissues might provide a rationale for the deleterious impact of CAA-secreted MMP11, favouring tumor progression. MMP11 overexpression also leads to increased circulating IGF1 levels and the activation of the IGF1/AKT/FOXO1 cascade, an important metabolic signalling pathway. Our data reveal a major role for MMP11 in controlling energy metabolism, and provide new clues for understanding the relationship between metabolism, cancer progression and patient outcome.

Highlights

Body weight was significantly decreased in young (8-week-old) and old (40-week-old) Mmp11-Tg mice compared to wild type mice (WT) littermates (Fig. 1b), and the difference more pronounced in older mice
Because of the altered mitochondria observed in the brown adipose tissue (BAT) of Mmp11-Tg mice, we addressed the direct effect of MMP11 on mitochondrial function in vitro. 3T3-L1 preadipocyte cells were treated for 24 h with active or inactive MMP11 recombinant proteins and key parameters estimating the functionality of oxidative phosphorylation (OXPHOS) were measured (Fig. 2g)
We demonstrated that MMP11 plays a systemic role in the regulation of glucose and lipid homeostasis, which led to insulin sensitivity and protection from diabesity

Summary

Introduction

Chemically-induced[12] or ras oncogene-induced[13] mouse tumor models have shown that stromal MMP11 is a key factor for tumor progression It lowers cancer cell death through anoikis during local invasion, favouring thereby cancer cell survival and implantation in connective tissues[14,15,16]. The molecular mechanisms involved remain largely unknown In this context, we hypothesized that the high amounts of MMP11 present in almost all invasive tumors might impact patient metabolism and energy homeostasis. Our data reveal that MMP11 impacts on lipid synthesis and in vivo storage in adipose tissues and liver, and protects Mmp11-Tg mice from diabesity Supporting this MMP11 metabolic function, Mmp11−/− mice[12] displayed a reverse phenotype with hallmarks of type 2 diabetes, most notably glucose intolerance and insulin resistance

Objectives

Results

Conclusion