Grant: Operating Grant

Excess accumulation of fat inside the abdomen, termed visceral obesity, is generally predominant in men. The presence of those large visceral fat stores has been closely linked to metabolic abnormalities which lead to diabetes and heart disease. Would it be possible to reduce fat storage in adipose tissue located inside the abdominal cavity and favor accumulation of fat tissues located under the skin, or subcutaneous fat? If so, this could delay the onset of diseases in men with abdominal obesity. This has in fact been done before with agents called thiazolidinediones, which have been widely used before their withdrawal due to adverse side effects. A new mode of action for anti-diabetes drugs is to block the synthesis cortisol, a steroid hormone favoring visceral fat storage, directly in adipose tissue. Our main postulate is that this can also be done with another type of steroid hormone, that is, the male sex hormone testosterone. While the testes are a main source of testosterone in men, we have evidence that adipose tissues can also generate a portion of their own testosterone from other hormones secreted by the adrenals (termed adrenal androgen precursors). We wish to prove that blocking testosterone synthesis or inactivation in some fat compartments will change the availability of the hormone in each fat compartment and will direct excess dietary lipids away from the visceral fat stores. To reach this goal, we will use cultures of adipose cells or explants obtained from various fat compartments of lean, overweight and obese men. We have access to pharmacological inhibitors that can block the reactions leading to testosterone synthesis. These inhibitors have never been tested in the context of obesity. We postulate that studying androgen production in fat will contribute to identify new targets for the remodeling of adipose tissue distribution in men.