TESTING TIMP3 AS A SWITCH TO BLOCK METABOLIC AND VASCULAR COMPLICATIONS OF OBESITY

Western lifestyle has increased the prevalence of metabolic disorders in several countries including Italy. The increased habit to eat foods rich in fat associated to the propensity to reduce daily exercise often result in development of obesity and progression to its metabolic complications such as insulin resistance and dyslipidemia that put the basis for appearance of diabetes, hyperthension and atherosclerosis, which provoke major cardiovascular accidents such as acute myocardial infarction and ictus. Moreover, it has become clear that in pathologies in which physical exercise is limited such as in many neuromuscular and neurological disorders, insulin resistance often appears as a co-morbid trait, with negative effects on long-term outcomes. Identification of factors contributing to concomitant onset of diabetes and atherosclerosis is therefore a major effort because they will allow to design drugs able to interfere at the same moment with the two diseases. We have recently identified one of these factors, a processed called membrane proteolysis which is regulated by a protein named Timp3. We have observed that Timp3 acts at the interface of cells to direct signal in order to maintain metabolic homeostasis and prevent excessive inflammation in muscle, liver, fat, aorta and other tissues. Timp3 is regulated by genetic mechanisms and we have identified one of them, that we will more intensively investigate in patients with metabolic diseases such as diabetes and atherosclerosis. In this research project the overall goal is to understand whether Timp3 protein may be used for the prevention of diabetes and atherosclerosis at preclinical level using appropriately designed animal models, a step that is necessary to obtain full evidence that a mechanism is valuable to be studied in depth in humans.