Targeting MT1-MMP: Therapeutic Opportunities In Obesity, Type 2 Diabetes And Other Associated Diseases

Obesity and diabetes are major causes of morbidity and mortality. Obesity is known to be the main risk factor for various non-communicable diseases, in particular type 2 diabetes. There is an ongoing need to identify non-invasive therapeutic approaches for the management of obese patients with type 2 diabetes to achieve their glycemic and weight loss goals.Recently, mutations in MT1-MMP (MMP14), a membrane bound metalloproteinase responsible for extracellular matrix remodeling and pericellular proteolysis, have been associated with human obese and diabetic traits. In this talk, the role of MT1-MMP in energy and glucose homeostasis and the molecular mechanism by which MT1-MMP regulates body weight and insulin sensitivity will be discussed. MT1-MMP contributes to the development of metabolic disorders through increasing energy intake and impairing insulin sensitivity. We found that MT1-MMP is a suppressor for GDF15-GFRAL signaling pathway, a newly identified central nervous system circuit that regulates metabolism and food intake in response to stress. In addition, MT1-MMP also impairs insulin signaling in the control of peripheral insulin sensitivity and glucose metabolism. These results indicate that MT1-MMP constitutes an important modulator of insulin sensitivity and energy homeostasis. Thus, targeting MT1-MMP represents potential therapeutics for the management of obesity and type 2 diabetes, two diseases with a need for combined treatment strategies.