Grant: Operating Grant

The accumulation of fat inside the abdomen, termed visceral obesity, is generally predominant in men but can also be found in some women. The presence of large intra-abdominal or visceral fat stores has been closely linked to the development of several metabolic abnormalities which lead to an increased risk of type 2 diabetes and cardiovascular disease. We still know little about the factors leading to preferential deposition of intra-abdominal fat in the presence of excess energy intake, but it is widely believed that sex hormones play a key role. In our previous studies, we have shown that an enzyme, AKR1C2, that is strongly expressed in adipose tissue is responsible for the inactivation of male sex hormones (androgens), and high levels of this enzyme have been associated with elevated amounts of fat inside the abdominal cavity. Accordingly, we also found that elevated androgen levels inhibit the recruitment of new fat cells. The objective of the present study is to further understand the role of such modulation of androgen action as a hormonal factor underlying abdominal obesity in humans. Several experiments will be performed in human fat cells from subcutaneous and visceral adipose tissue samples surgically-obtained in men. A transgenic mouse model will also be created. We postulate that inactivation of male sex hormones in fat tissue may represent a critical regulatory aspect underlying the most harmful form of obesity in humans: abdominal-visceral obesity. Modulation of this pathway could possibly become a drug target in the current obesity epidemic.