Therapeutic Perspectives of Fatty Acid Binding Proteins

The nutrient content of diet has a profound influence on a number of vital physiological pathways. Furthermore, a strong link exists between the dietary trends and a number of common diseases such as cancer, diabetes and atherosclerosis. We approach the molecular basis of these interactions by focusing on fatty acid-mediated transcriptional regulation in cells and the biological role of fatty acid-binding proteins (FABP) as lipid chaperones involved in intracellular lipid trafficking. We have developed several mice models that are deficient in adipocyte/macrophage FABPs and demonstrated that these animals were protected from some of the most detrimental effects of dietary intake of high levels of calories and fatty acids through alterations in the gene expression pattern of adipocytes, macrophages and systemic metabolic responses. We have so far demonstrated that FABPs are central to many components of the metabolic syndrome, including obesity, insulin resistance, type 2 diabetes and cardiovascular disease. These proteins are also proximal to generation of the inflammatory responses, especially upon exposure to lipids. Using FABP-deficient animals and cells as model systems, we are trying to establish the components of the signaling pathway that is controlled by FABPs and the mechanisms by which these pathways are linked to inflammatory and metabolic responses. We hope to generate insights into the mechanisms leading to obesity, diabetes and atherosclerosis and create novel preventive and therapeutic opportunities.

Our mechanistic studies so far indicate that these lipid chaperone proteins are proximal to the generation of inflammatory responses, especially upon exposure to lipids, and couple lipotoxicity to organelle function. More recently, we discovered that aP2 is secreted from adipocytes in response to lipolytic stimulation and during fasting, and acts on the liver to stimulate glucose production. Circulating aP2 levels are elevated in obese mice and humans, and high levels of circulating aP2 are strong and independent risk factors for metabolic disease. Remarkably, we demonstrated that aP2 neutralization with an antibody improved glucose tolerance and insulin sensitivity in obese mice. This strengthens our hypothesis that aP2 is a promising target for the development of new diabetes therapeutics.