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.
Charles KN, Li M, Engin F, Arruda AP, Inouye K, Hotamışlıgil GS. Uncoupling of Metabolic Health from Longevity through Genetic Alteration of Adipose Tissue Lipid-Binding Proteins. Cell Reports. 2017 Oct; DOI:10.1016/j.celrep.2017.09.051. Abstract
Burak MF, Inouye KE, White A, Lee A, Tuncman G, Calay ES, Sekiya M, Tirosh A, Eguchi K, Birrane G, Lightwood D, Howells L, Odede G, Hailu H, West S, Garlish R, Neale H, Doyle C, Moore A, Hotamışlıgil GS. Development of a therapeutic monoclonal antibody that targets secreted fatty acid–binding protein aP2 to treat type 2 diabetes. Science Translational Medicine 2015 December 23 doi:10.1126/scitranslmed.aac6336. Abstract | PDF
Erikci Ertunc M, Hotamışlıgil GS. Lipid Signaling and Lipotoxicity in Metabolic Inflammation: Indications for Metabolic Disease Pathogenesis and Treatment. Journal of Lipid Research. 2016 Jun; DOI:10.1194/jlr.R066514. Abstract
Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, MacRae FL, Sulsky R, Robl JA, Parker RA, Hotamışlıgil GS. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature, 2007, 447:959-965. Abstract |PDF
Shum BOV, Mackay CR, Gorgun CZ, Frost MJ, Kumar RK, Hotamışlıgil GS, Rolph MJ. The adipocyte fatty acid–binding protein aP2 is required in allergic airway inflammation. JCI, 2006, 116(8):2183–2192. Abstract | PDF
Cao H, Maeda K, Gorgun CZ, Kim HJ, Park SY, Shulman GI, Kim JK, Hotamışlıgil GS. Regulation of metabolic responses by adipocyte/ macrophage fatty acid–binding proteins in leptin-deficient mice. Diabetes, 2006, 55(7):1915-22. Abstract |PDF
Tuncman G, Erbay E, Hom X, De Vivo I, Campos H, Rimm EB, Hotamışlıgil GS. A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci USA, 2006, 103(18):6970-5. Abstract| PDF