GENETIC AND PHYSIOLOGICAL REGULATION IN BROWN ADIPOCYTES

其长期目标是了解棕色脂肪组织(BAT)的生理和发育规律。棕色脂肪组织(BAT)的生热活性受多种生理信号的调节，包括冷暴露、冬眠唤醒和过度摄食。BAT独特的生热特性是通过BAT特异性解偶联蛋白(UCPI)的作用使线粒体呼吸和氧化磷酸化解偶联而产生的。因为产热相当于能量消耗，蝙蝠在生物体中可以起到确保恒温和能量平衡的双重作用。在没有过度吞噬的情况下，在转基因小鼠中去除BAT会导致肥胖，证实了BAT在能量平衡中的重要作用。肥胖是糖尿病、高血压和冠状动脉疾病发展的主要危险因素。对蝙蝠生长和发育控制机制的深入了解可能会导致开发新的治疗方法来解决肥胖问题。UCP1控制蝙蝠的生热活性，是棕色脂肪细胞的决定性基因产物。因此，控制UCP1表达的调控因子可能是棕色脂肪细胞分化和生理调节的基本决定因素。来自棕色脂肪细胞瘤的HIB-1B细胞系分化为适当表达UCP1基因的棕色脂肪细胞。UCP1增强子位于-2.5~-2.3kb之间，能够将高水平的基因表达导向转基因小鼠的BAT，其表达受冷暴露和禁食/再摄食等生理刺激的调控。具体目标1将利用HIB-1B细胞系统地鉴定该增强子中的顺式作用元件。特殊目的2将研究一种新的蝙蝠辅活化子PGC1的调节。具体目标3研究cAMP和维甲酸反应元件在调节冷暴露和禁食/喂养反应中的作用。

The long-term objective is to understand the physiologic and developmental regulation of brown adipose tissue (BAT). The thermogenic activity of brown adipose tissue (BAT) is regulated in response to a number of physiologic signals including cold- exposure, arousal from hibernation and overfeeding. The unique thermogenic properties of BAT derive from the uncoupling of mitochondrial respiration and oxidative phosphorylation through the action of the BAT-specific uncoupling protein (UCPI). Because heat production is equivalent to energy expenditure, BAT can play a dual role in the organism of ensuring homeothermy and energy balance. Ablation of BAT in transgenic mice causes obesity in the absence of hyperphagia confirming the important role of BAT in energy balance. Obesity is a major risk factor for the development of diabetes, hypertension and coronary artery disease. A deeper understanding of the mechanisms controlling BAT growth and development may lead to the development of novel therapeutic approaches to the problem of obesity. UCP1 controls the thermogenic activity of BAT and is the defining gene product of the brown adipocyte. Thus, the regulatory factors controlling UCP1 expression are likely to be fundamental determinants of brown adipocyte differentiation and physiologic regulation. The HIB-1B cell line derived from a brown fat cell tumor differentiates into brown adipocytes that appropriately express the UCP1 gene. The UCP1 enhancer located at -2.5 to -2.3 kb is capable of directing high level gene expression to BAT of transgenic mice and expression is regulated by physiological stimuli such as cold exposure and fasting/refeeding. Specific aim 1 will utilize the HIB-1B cells to systematically identify the cis-acting elements within this enhancer. Specific aim 2 will examine the regulation of a novel BAT coactivator PGC1. Specific aim 3 examines the role of cAMP and retinoic acid response elements in mediating the response to cold exposure and fasting/feeding.