Grant: Operating Grant

There is now considerable evidence that obesity, and in particular abdominal obesity, is a risk factor for cardiovascular disease, diabetes and hypertension. The exact reason for this association is not clear. However, there is currently a wide interest in understanding the factors that control how and where the dietary fat is deposited in fat tissue. Fat is released into the bloodstream to provide an energy source to other tissues. There are many different fat depots in the body and the efficiency of fat deposition and release of fat into the bloodstream varies widely. However, if too much fat is released, then the amount exceeds what is required by the muscle and other tissues for energy, and the excess may cause problems in both the liver and in the arteries. Our studies have focused on determining the role of a hormone (ASP) produced by fat tissue in increasing the efficiency of fat storage. In mouse models that do not have ASP, the mice are leaner, with reduced fat tissue in spite of eating more food. This increase in food intake is counterbalanced by an increase in energy expenditure. Our present goals are to understand the mechanisms in the body which change in order to increase energy expenditure and reduce energy storage in these mice. One of the primary questions is: Is the ASP acting at the level of the brain (centrally) or peripherally (on adipose and muscle)? We will also determine the effect of providing too much ASP on the mice: we hypothesize that this will result in increased fat storage and can lead to problems in insulin sensitivity (important for sugar regulation) as well as inflammatory response (abnormal immune activation). We are using a combination of animal studies and genetic analysis to identify the sequence of steps involved. These studies will help us to understand the regulation of fat storage in humans, and future studies may allow us to design pharmacological compounds to control obesity and reduce its profound health consequences.