Our primary research interests in the field of Diabetes and Obesity are directed to the study and characterization of lipid droplet surface proteins and their role in regulating the fat storage compartment in adipose tissues as well as in non-adipose tissues (liver, muscle and heart). Clear and convincing evidence links type 2 diabetes mellitus (T2D) with obesity. Elevated non-esterified free fatty acids (NEFA) levels, caused by a dysregulation of adipose tissue lipolysis, may serve the link between obesity and risk for T2D. Lipolysis is needed to release stored NEFA during increased energy demand but excessive release contributes to insulin resistance, excess NEFA are now being stored by non adipose tissues, ill equipped to handle surplus fat. The role of ectopic fat deposition, the accumulation of lipid droplets in non-adipose tissues, is recognized as a strong prognostic factor for the development of insulin resistance. Formation of lipid droplets maintains cellular NEFA homeostasis by storing excess NEFA as triglyceride and releasing it when needed. The ability to store excess NEFA provides protection from â?olipotoxicityâ? leading to inflammation, insulin resistance and in extreme cases cellular apoptosis. Thus the mechanisms regulating cellular lipid droplet formation and turnover are clearly important yet poorly understood. This regulation appears to be mediated by the protein coat surrounding all lipid droplets, which include at least one member of the PAT protein family originally named for a triad of Perilipin, ADRP and Tip47 with high primary sequence homology and conservation across species and now including S3-12, and PAT-1. Perilipin (Peri) and S3-12 are confined to adipose, while ADRP, Tip47, LSPD-5 are ubiquitously distributed. To date, a functional role regulating lipolysis in adipocytes has been shown only for Peri. Mylaboratory goals are to understand the functional importance of three functionally uncharacterized PAT proteins, ADRP, TIP47 and LSPD-5 in lipid droplet metabolism in non-adipogenic tissues using loss of function with RNAI techniques and this work is supported by an RO1. Another important goal of my laboratory is to develop methodologies to study in situ the interactions between lipid droplet surface proteins and proteins involved in lipid metabolism (lipogenesis and lipolysis). More specifically, I received an American Diabetes Carrier Award to characterize the molecular events underlying the critical role of Perilipin as a gatekeeper to lipases in adipose tissue by adapting novel fluorescent techniques (FRAP, FRET and FLIP) to the study of Perilipin and lipases interactions at the surface of the lipid droplet. Most recently, I have been collaborating with scientists at the Max Planck institute and at NIDDK to identify genes involved in the lipid droplet biogenesis and metabolism using RNAi technology.
Grants and Contracts:
"Role of PAT Proteins in Ectopic Fat"