Grant: Operating Grant

Obesity is a major public health issue leading to major costs emerging from the treatment of cardiovascular, metabolic (type 2 diabetes) and respiratory diseases. Obesity is characterized by an imbalance between energy intake and energy expenditure, which is incidentally in agreement with the latin root of obesity "obedere", meaning "to eat in excess". Despite the progress made in our understanding of the mechanisms involved in the regulation of energy balance, there are still several aspects of that regulation, which need to be elucidated. One aspect that deserves attention is the mechanism whereby the brain controls energy intake and energy expenditure, which are the two inescapable determinants of energy balance. The mechanistic target of rapamycin (mTOR) is a protein that senses nutrients and growth factors and regulate anabolic processes in various organs, including the brain. mTOR nucleates distinct multiprotein complexes termed mTORC1 and mTORC2. Hypothalamic mTORC1 is capable of influencing food intake and certain components of energy expenditure such as brown adipose tissue thermogenesis. Its activity is reduced by fasting and induced by refeeding, whereas anorectic signals such as leptin, insulin and ghrelin require mTORC1 activity to exert their inhibitory effects on feeding. Recently, we have identified DEP-domain containing mTOR-interacting protein (DEPTOR) as a key modulator of hypothalamic mTORC1. We have evidence that DEPTOR may be sensitive to variations in energy stores and therefore could play a significant role in the regulation of energy balance. Whether DEPTOR could affect the metabolic profile of the obese by modulating mTOR activity has never been tested. This research proposal aims to investigate the role DEPTOR in the regulation of energy balance using molecular approaches, genetically-engineered mice and advanced molecular imaging methodologies.