title: Matrix metalloproteinase 11 protects from diabesity and promotes metabolic switch.
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.
authors.affiliation: Department of Functional Genomics and Cancer, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC)/ CNRS UMR 7104/ INSERM U 964/ Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.|Laboratoire de Biochimie et Biologie Moléculaire, Pôle de Biologie, Hôpitaux Universitaires de Strasbourg, 1 place de l'hôpital, 67098 Strasbourg Cedex, France.
authors.forename: Nassim
authors.initials: N
authors.lastname: Dali-Youcef
authors.affiliation: Department of Translational Medicine and Neurogenetics, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC)/ CNRS UMR 7104/ INSERM U 964/ Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.|Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Hnia
authors.affiliation: Department of Functional Genomics and Cancer, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC)/ CNRS UMR 7104/ INSERM U 964/ Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Blaise
authors.affiliation: Electron microscopy platform, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC)/ CNRS UMR 7104/ INSERM U 964/ Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.affiliation: Institut Pluridisciplinaire Hubert Curien, UMR 7178, CNRS-IN2P3-INC-INEE, Université de Strasbourg, 23 rue du Loess-BP28, 67037 Strasbourg cedex 2, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanc
authors.affiliation: INSERM, U1016, Institut Cochin/ CNRS, UMR8104/ Université Paris Descartes, Sorbonne Paris Cité, 75014, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.affiliation: Department of Functional Genomics and Cancer, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC)/ CNRS UMR 7104/ INSERM U 964/ Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Tomasetto
authors.affiliation: Department of Functional Genomics and Cancer, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC)/ CNRS UMR 7104/ INSERM U 964/ Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Rio
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control*; D004734:Energy Metabolism; D015870:Gene Expression; D055786:Gene Knockout Techniques; D006019:Glycolysis; D053507:Matrix Metalloproteinase 11 / Q000378:metabolism*; D024821:Metabolic Syndrome; D051379:Mice; D009765:Obesity / Q000517:prevention & control; D010085:Oxidative Phosphorylation
chemical_list: D053507:Matrix Metalloproteinase 11