PPAR-gamma Agonists, Weight Gain and Fat Redistribution

描述(由申请人提供)： 本次研究生涯奖(K01)的候选人计划通过这项申请接受进行动物和临床研究的额外培训，特别强调学习脂肪细胞生物学研究中常用的细胞和分子生物学技术。她的最终目标是获得独立的资金，继续她在脂肪组织代谢和发育方面的研究，因为它与肥胖和代谢综合征有关。纽约肥胖研究中心完全有能力在这些领域为她提供进一步的指导和培训。 噻唑烷二酮类药物是治疗2型糖尿病的常用药物，可改善胰岛素敏感性和高脂血症，部分是通过诱导脂肪组织储存的脂肪重新分配来实现的。这些药物是转录因子过氧化物酶体增殖物激活受体伽马(PPAR伽马)的配体，PPAR伽马是脂肪细胞分化的调节因子。体重增加是这些药物的常见副作用，但目前尚不清楚哪些人在治疗期间最容易体重增加。这些PPAR伽玛激动剂也被证明在2型糖尿病患者中将脂肪组织从内脏重新分布到皮下。目前尚不清楚PPARγ激动剂引起的脂肪组织代谢的改变是导致脂肪重新分布和改善胰岛素敏感性的原因。 本应用的具体目的如下：(1)确定PPARγ激动剂介导的非糖尿病肥胖胰岛素抵抗受试者的脂肪组织代谢和呼吸商的变化。(2)研究PPAR-γ激动剂在体外对不同病态肥胖者腹部和内脏皮下脂肪代谢和基因表达影响的区域性差异。(3)研究PPARγ激动剂是否介导了脂肪组织的变化，这些变化可能会改变啮齿动物在摄入高脂饮食后体重增加的易感性。 这些研究的结果将有助于医生预测哪些患者对噻唑烷二酮治疗的反应最好，并将有助于制定策略，将PPAR伽马激动剂治疗期间和治疗后的体重增加降至最低。

DESCRIPTION (provided by applicant): 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.