Improving MC4R signaling via isoform selective PI3K targeting to fight melanocortin obesity syndrome

In Europe, childhood obesity has increased by 10 times from the 70s (in Italy it is estimated that 12.3 percent of children are obese). Obesity is a clinical condition that almost always favors other diseases, including cardiovascular disorders, diabetes mellitus type 2, dysfunction of the osteo-articular system, stroke, sleep apnea syndrome and certain types of cancer. In most cases, obesity is caused by an unbalanced diet and sedentary lifestyles. However in a small but significant percentage of cases, the "cause" is in the genes. In about 6 percent of patients, obesity is in fact the primary manifestation of a genetic disease. The deficit of the melanocortin-4 receptor (MC4R) is the most common form of congenital obesity up to now identified. Patients carrying MC4R mutations are characterized by severe obesity, increased bone mineral density, hyperphagia (i.e. an uncontrolled increase in appetite), severe hyperinsulinemia and abnormal maintenance of reproductive function. The prevalence of MC4R mutations has been estimated between 0.5 and 6 percent of obese adults, with higher levels in populations with severe obesity in childhood-onset and variability among different ethnic groups. The estimated incidence of this rare disease is 1-5 cases per 10,000. The development of drugs able to modulate the activity of MC4R may result in effective treatments for this type of genetic defect. Thus, in this project we intend to explore a new therapeutic strategy designed to enhance the activity of MC4R in obese patients in which its function is reduced by a genetic alteration.