A search for new pathways in the reversal and prevention of obesity and type 2 diabetes

Obesity is a chronic disease that mainly develops in sedentary individuals, over-consuming a Western diet, rich in salt, sugar and fat. Obesity is a major cause of several life threatening health risks, such as type 2 diabetes (T2D). The currently available drugs have rather disappointing long-term effects. Gastric bypass procedures (GBP) have turned out to be a very effective treatment for obesity and associated T2D with a maintained effect over time. Obviously, surgery cannot be put forward as a primary treatment as it implies significant risks and costs. The exact mechanisms of the beneficial effects of GBP on glucose homeostasis remain unknown. The first aim is to gain insight into how GBP improve insulin sensitivity and beta cell function as this might lead to new targets for less invasive treatments, such as pharmacotherapy. The exact mechanisms linking obesity to T2D also remain to be elucidated. Genetic studies pointed out a role for several genes, including Wnt-related genes, and for changes in DNA methylation, which can alter gene expression. The second aim is to study T2D- and obesityinduced changes in DNA methylation and evaluate potential changes after GBP. This will point out new genes involved in obesity and can reveal a methylation profile, predictive for the clinical outcome of surgery. In the last aim, we will assess whether Wnt genes are involved in the remission of obesity and T2D following GBP. If so, these genes might be valuable drug targets.