Matrix metalloproteinase 11 protects from diabesity and promotes metabolic switch

• Published in: Scientific reports 2016-04, Vol.6 (1), p.25140-25140, Article 25140
• Main Authors: Dali-Youcef, Nassim, Hnia, Karim, Blaise, Sébastien, Messaddeq, Nadia, Blanc, Stéphane, Postic, Catherine, Valet, Philippe, Tomasetto, Catherine, Rio, Marie-Christine
• Format: Article
• Language: English
• Subjects: 14/28; 14/63; 38/39; 631/443/319/1642/2037; 64/110; 64/60; 692/163; 82; 82/80; Adipocytes; Adipogenesis; Adipose tissue; AKT protein; Animals; Biochemistry, Molecular Biology; Cancer; Carcinoma; Cell survival; Diabetes mellitus; Diabetes Mellitus, Type 2 - prevention & control; Energy balance; Energy Metabolism; Fibroblasts; FOXO1 protein; Gene Expression; Gene Knockout Techniques; Glycolysis; Homeostasis; Humanities and Social Sciences; Insulin-like growth factor I; Life Sciences; Matrix metalloproteinase; Matrix Metalloproteinase 11 - metabolism; Mesenchyme; Metabolic disorders; Metabolic Syndrome; Metabolism; Metalloproteinase; Mice; Mitochondria; multidisciplinary; Obesity - prevention & control; Oxidative Phosphorylation; Oxidative stress; Phosphorylation; Proteinase; Rodents; Science; Science (multidisciplinary); Signal transduction
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep25140

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.