Grant: Project Grant

More than 25% of Canadians are obese. Obesity is the major risk factor for type 2 diabetes, which affects approximately 8% of Canadians. Elevated levels of circulating and tissue fat predispose obese individuals to develop type 2 diabetes. Furthermore, fatty liver is nowadays the major cause of liver disease and excess circulating fat predisposes obese individuals to develop cardiovascular disease. Our objective is to investigate the mechanisms of fat-induced abnormalities in sugar and fat handling in the liver, which is a very important organ for the maintenance of normal blood sugar and fat levels. Based on our preliminary data, we hypothesize that sugar and fat handling by the liver are regulated by two different pathways that branch from the same fat-activated molecule. We will measure liver production of sugar and fat and liver fat accumulation under fasting conditions and after challenging with fat administered by vein or diet. This will be done in mice that lack key molecules of these two pathways and their activating molecule, and in control mice. Liver tissue, which cannot be obtained from humans, will allow us to assess these two pathways and their activating molecule. Thus, we will delineate a roadmap of interest for manipulation by the pharmaceutical industry. By understanding the mechanisms of fat-induced abnormalities in sugar and fat handling by the liver, we will identify targets for nutrient and drug intervention to prevent type 2 diabetes, fatty liver, and cardiovascular disease. Thus, our investigation will help mitigate the public health impact of obesity.