Lipotoxicity, the link between obesity and the Metabolic Syndrome: pathogenic mechanisms and therapeutic strategies.

Obesity and obesity-associated diabetes are becoming more and more common. These days we see more obese children developing the same type of diabetes that previously was seen exclusively seen in adults. Complications related to obesity and diabetes are presenting more frequently as this prematurely obese population ages. Obese and diabetic individuals are at high risk of dying at an early age, principally from heart attacks. The ideal strategy would be to prevent people becoming obese, but it is clear that obesity prevention, be it by public health measures or drug treatments, is failing. Our final goal is to prevent obese people from becoming diabetic and having heart attacks. To do this we investigate how being obese causes diabetes or heart disease and how to tackle or prevent these diseases in an obese state. We think that the main problem is that obese people fail to store fat in the correct place, which is adipose tissue. When adipose tissue becomes full then fat spills over into other organs such as the liver. When fat accumulates in organs such as muscle or liver it has toxic effects, a process we call lipotoxicity. In this grant application we study how these toxic effects of fat occur, and what can we do to treat it or prevent it. For this we need to use mouse models, to fully understand how the whole body deals with excess fat. The strategies we propose include; a) to make the adipose tissue healthier so it can trap fat better, b) increasing the capability of organs (such as muscle and even adipose tissue itself) to burn fat. While this may not cure obesity it may at least prevent people from dying from it. We hope our research will help to control the coming epidemics of heart attacks, diabetes and strokes caused by obesity.

The aim of this grant is to understand the metabolic events linking obesity and insulin resistance and to provide scientific support for strategies to treat/prevent these conditions. Our hypothesis is that inappropriate lipid storage in tissues other than adipose is the major underlying factor linking obesity and insulin resistance. The concept that ectopic lipid deposition causes insulin resistance is also known as lipotoxicity. We have developed two main concepts based on the lipotoxicity hypothesis: a) Improving the capacity for lipid storage in adipose will protect against insulin resistance and diabetes. b) In the advent of a failure to store lipid appropriately in adipose tissue then mitochondrial oxidation of lipids will protect against diabetes. This grant will investigate these concepts. The first concept will be addressed by investigating the ability of Prostaglandin F2a in promoting preadipocyte proliferation and therefore enabling increased adipose tissue storage capacity which in turn should prevent the development of insulin resistance. The second concept will be addressed by investigating the role of coactivators PGCs and bone morphogenic protein 8b (BMP8b) in regulating mitochondrial oxidation and preventing lipotoxicity through burning excess lipid. The components of the applications make extensive use of animal models, as well as sophisticated physiological phenotyping tools. This information will be combined with molecular studies using a systems biology approach funded through current FP6 Hepadip and FP7 Etherpath grants to evaluate the global impact of these genetic modifications on energy homeostasis.