PPAR-gamma Agonists, Weight Gain and Fat Redistribution

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EXCEED THE SPACE PROVIDED. The candidate for this Research Career Award (K01) plans through this application to receive additional training in conducting animal and clinical research, with a special emphasis in learning cell and molecular biology techniques commonly employed in studying adipocyte biology. Her ultimate goal is to attain independent funding to continue her research in adipose tissue metabolism and development as it relates to obesity and the metabolic syndrome. The New York Obesity Research Center is well-equipped to offer her further instruction and training in these areas. Thiazolidinediones, drugs commonly used in the treatment of type 2 diabetes mellitus, improve insulin sensitivity and hyperlipidemia partly through inducing repartitioning of lipid towards adipose tissue storage. These drugs are ligands for the transcription factor peroxisome proliferator activated receptor gamma (PPAR gamma), which is a regulator of adipocyte differentiation. Weight gain is a common side effect of these drugs, but it is unclear which individuals are most susceptible to gaining weight during treatment. These PPAR gamma agonists also have been shown to redistribute adipose tissue from visceral to subcutaneous compartments in type 2 diabetic subjects. It is not known which PPAR gamma agonist-induced changes in adipose tissue metabolism are responsible for the fat redistribution and improvement in insulin sensitivity. The specific aims of this application are as follows: (1) To determine changes in adipose tissue metabolism and respiratory quotient that accompany PPAR gamma agonist-mediated increased insulin sensitivity in nondiabetic obese insulin-resistant human subjects. (2) To examine regional variation in PPAR gamma agonist-mediated effects in vitro on metabolism and gene expression, in different subcutaneous abdominal and visceral fat depots from morbidly obese human subjects. (3) To examine whether PPAR gamma agonists mediate changes in adipose tissue that may alter susceptibility to weight gain in rodents when exposed to a high fat diet, post-treatment. The results of these studies will assist physicians in predicting which patients will best respond to thiazolidinedione therapy, and will help to develop strategies to minimize weight gain during and after treatment with PPAR gamma agonists. PERFORMANCE SITE ========================================Section End===========================================