Autotaxin-lysophosphatidic acid signaling in obesity-related heart disease

Obesity is a serious health problem in Canada. A main complication of obesity is insulin resistance, wherein the hormone insulin loses its ability to stimulate the uptake of blood sugar in tissues. Insulin resistance often leads to type 2 diabetes and can damage heart muscle cells, giving rise to heart muscle weakening. If untreated, obesity and diabetes-induced heart muscle weakening may lead to heart failure and early death. It is important to understand why people with obesity or diabetes develop heart muscle weakening and what can be done to prevent and treat this disease. The objective of this research proposal is to study what is happening in heart muscle cells of obese people with insulin resistance or diabetes that leads to heart muscle weakening. We will examine the role of a small fat molecule, lysophosphatidic acid (LPA), in this process since we have previously shown that the molecular machinery that produces LPA is stimulated in people and mice with obesity. We will test through experiments on animal cells and obese mice with obesity/diabetes, whether high LPA levels and heightened communication between LPA and heart muscle cells cause heart muscle weakening and how this occurs. We will test whether LPA hinders insulin function in heart muscle cells and changes the use of sugar and fats as energy source in the heart. We will also test whether high LPA reduces the function of mitochondria, powerhouses of heart muscle cells. Finally, we will test whether blocking LPA communication to heart muscle cells can protect from obesity-induced heart muscle weakening in mice. This research will allow us to better understand obesity and diabetes-induced heart muscle weakening and develop new and better ways to treat this disease. In doing so, our research is expected to help lower the burden of obesity and diabetes on the Canadian health care system.