CHARACTERIZATION OF GENES WHICH ARE DIFFERENTIALLY REGULATED IN THE WHITE ADIPOSE TISSUE (WAT) IN OBESITY: STUDIES ON THEIR ROLE IN METABOLISM AND IN THE ONSET OF OBESITY ASSOCIATED COMPLICATIONS

The genetic component of obesity has been widely demonstrated, but only a small fraction of the genes involved in its onset were characterized and this limits the possibility of devising useful pharmaceutical strategies to treat the disorder and the associated complications including diabetes cardiovascular diseases, dyslipidemia. This project is aimed at identifying the molecular cellular events participating to the onset of obesity and of its comorbidities. Our studies are mainly focused on the changes occurring in the white adipose tissue (WAT) during obesity. A particular attention is dedicated to the chronic inflammatory state often associated to this condition which is mainly driven by a massive macrophage infiltration into WAT. Our studies lead to the identification of two genes, a protease named cathepsin K (ctsk) and an inflammatory protein called haptoglobin (hp) which are upregulated in the WAT of obese individuals. We recently proved that ctsk regulates the capacity of the adipose tissue to accumulate triglyceriderides both in the very young and in the adult upon exposure to high calories diet. In obese mice deficient for this factor dyslipidemia is partially prevented. Experiments are in progress do determine which cellular and molecular pathway are involved in these phenomena. Our aim is to develop (in collaboration with a pharmaceutical company) inhibitors directed against ctsk which could be used in the treatment of dyslipidemia. We proved that Hp, a novel adipocyte secreted factor, is involved in the recruitment of macrophages. Studies will be performed to determine which receptors on macrophage surface allow this interaction. These may have important implications to prevent macrophage infiltration, i.e. the onset of an altered inflammatory status. Our data indicate that Hp deficiency in obese mice is associated with the prevention of hepatic steatosis and insulin resistance. We are developing biological tools to further investigate this issue.