REGULATION AND ACTIVATION OF STATS IN ADIPOCYTES

脂肪细胞是高度特化的细胞，在脊椎动物体内的脂质稳态和维持能量平衡中发挥核心作用。 这些细胞在营养丰富时期以甘油三酯的形式储存能量，并在营养缺乏时以游离脂肪酸的形式释放能量。 与脂肪细胞数量或功能改变相关的病理状况包括肥胖症和几种脂肪营养不良综合征。 肥胖是一种脂肪组织的过度积累，是一种常见的疾病，影响超过30%的美国人。 在人类中，肥胖是非胰岛素依赖型糖尿病（NIDDM）、高血压和冠状动脉疾病的独立危险因素，并且是发病率和死亡率的主要贡献者。 最近的研究表明，肥胖及其相关疾病可能与控制脂肪细胞中代谢基因表达的调节机制的崩溃有关。 通过鉴定调节脂肪细胞分化和基因表达的转录因子，对这些调节过程的理解取得了重大进展。 迄今为止，两个转录因子家族的成员，C/EBP（C/AAAT增强子结合蛋白）和过氧化物酶体激活受体（过氧化物酶体激活受体）已被证明在脂肪细胞分化过程中被诱导，并在脂肪特异性基因的调节中发挥关键作用。 我们最近的研究表明，在脂肪细胞分化过程中诱导了一个额外的转录因子家族。 STAT（信号转导和转录激活因子）包括存在于静息细胞的细胞质中的转录因子家族。与C/EBP或PPARs不同，STAT可以快速激活以控制基因表达。 以与C/EBPalpha和PPARgamma两者等同的方式，三个STAT家族成员的表达与脂质蓄积相关。 由于STAT家族成员具有独特的组织分布，并且在脂肪细胞中高度表达，因此我们假设STAT在脂肪细胞基因表达的调节中起关键作用。 为了验证这一假设，我们将研究脂肪细胞中STAT的调节和激活。 我们还设计了一组实验来阐明这些蛋白在脂肪细胞中的功能。这些研究可能导致对调节能量稳态的分子机制的深入了解，并可能对肥胖和NIDDM的潜在缺陷产生深远的影响。

Adipocytes are highly specialized cells which play a central role in lipid homeostasis and the maintenance of energy balance in vertebrate organisms. These cells store energy in the form of triglycerides during periods of nutritional abundance and release it in the form of free fatty acids at times of nutritional deprivation. Pathological conditions associated with altered adipocyte cell number or function include obesity and several lipodystrophy syndromes. Obesity, an excessive accumulation of adipose tissue, is a common disorder which affects over 30 percent of Americans. In humans, obesity is an independent risk factor for non-insulin dependent diabetes mellitus (NIDDM), hypertension, and coronary artery disease and is a major contributor to morbidity and mortality. Recent studies suggest that obesity and its related disorders may be linked to a breakdown in the regulatory mechanisms which control the expression of metabolic genes in adipocytes. Significant advances toward an understanding of these regulatory processes have been made by the identification of transcription factors which regulate adipocyte differentiation and gene expression. To date, members of two transcription factor families, C/EBP (C/AAAT Enhancer Binding Proteins) and PPAR (Peroxisome Proliferator Activated Receptors) have been shown to be induced during adipocyte differentiation and play a critical role in the regulation of fat-specific genes. Our recent investigations have demonstrated that an additional family of transcription factors are induced during adipocyte differentiation. The STATs (Signal Transducers and Activators of Transcription) comprise a family of transcription factors which reside in the cytoplasm of resting cells. Unlike either C/EBPs or PPARs, STATs can be rapidly activated to control gene expression. In a manner equivalent to both C/EBPalpha and PPARgamma, expression of three STAT family members correlates with lipid accumulation. Since STAT family members have unique tissue distributions and are highly expressed in adipocytes, we hypothesize that STATs play a key role in the regulation of adipocyte gene expression. To test this hypothesis, we will examine the regulation and activation of STATs in adipocytes. We have also designed a set of experiments to elucidate the function of these proteins in adipocytes. These studies may lead to insights into the molecular mechanisms regulating energy homeostasis and may have a profound impact on the defects underlying obesity and NIDDM.