Regulation of Thermogenesis in Adipocytes Through TRPA1

项目摘要 肥胖是一种全球流行病，与许多毁灭性疾病有关，如2型糖尿病和 心脏病对肥胖和脂肪组织功能的研究可以帮助我们理解这些疾病， 确定可能的预防战略。产热性脂肪细胞是一种脂肪细胞， 对冷刺激作出反应的产热程序。这种产热程序的上调导致 脂肪细胞以热量的形式分散能量，而不是储存能量。最近， 在成年人中鉴定，研究表明，人类中活跃的产热脂肪细胞是 与改善的代谢参数相关，这表明这些细胞是糖尿病的一个有希望的靶点。 和肥胖治疗。我的初步数据显示用瞬时受体处理脂肪细胞 潜在的阳离子通道A1（TRPA1）激动剂肉桂醛（CA）和烯丙基异硫代甜菜碱（AITC）增加 产热基因表达我假设TRPA1介导脂肪细胞的产热反应， TRPA1激动剂将提高耐寒性并对抗肥胖。我建议研究生热作用- 小鼠和人类产热脂肪细胞对TRPA 1激活的反应的相关变化， TRPA 1激动或敲除对体内调节产热和葡萄糖代谢作用。 目的1：表征TRPA 1介导的在细胞内产热调节的机制。 细胞水平。我的初步数据显示小鼠和人类的皮下脂肪细胞 上调产热基因表达以响应用TRPA 1激动剂CA和AITC处理。 此外，小鼠和人类皮下细胞均上调产热基因表达， 冷暴露。在这个目标中，我将描述TRPA 1激动上调的机制 通过研究TRPA 1激动在调节线粒体和脂肪细胞中的作用， 功能和脂肪分解。 目的2：确定TRPA1在调节全身代谢中的作用。过去的研究 表明在产热脂肪中诱导产热可以对抗肥胖并改善葡萄糖 新陈代谢.在这个目标中，我将使用小鼠模型来研究TRPA1敲除或激动在小鼠中的作用。 调节对冷的产热反应和改善葡萄糖代谢的作用， TRPA 1激动剂口服灌胃调节脂肪组织产热和对抗高脂饮食 诱发性肥胖

Project Summary Obesity is a global epidemic that is linked to a number of devastating diseases, such as type 2 diabetes and heart disease. Studies of obesity and adipose tissue function can help us comprehend these diseases and identify possible strategies to prevent them. Thermogenic adipocytes are a type of fat cell that upregulates a thermogenic program in response to cold stimuli. This upregulation of the thermogenic program causes adipocytes to disperse energy as heat, as opposed to storing it. Thermogenic adipocytes recently have been identified in adult humans, and studies have shown that active thermogenic adipocytes in humans are correlated with improved metabolic parameters, suggesting that these cells are a promising target for diabetes and obesity therapies. My preliminary data show that treatment of adipocytes with the transient receptor potential cation channel A1 (TRPA1) agonists cinnamaldehyde (CA) and allyl isothiosyanate (AITC) increases thermogenic gene expression. I hypothesize that TRPA1 mediates a thermogenic response in adipocytes and that TRPA1 agonism will improve cold tolerance and counteract obesity. I propose to study the thermogenesis- associated changes in mouse and human thermogenic adipocytes in response to TRPA1 activation and the effect that TRPA1 agonism or knockout has on regulating thermogenesis and glucose metabolism in vivo. Aim 1: To characterize the mechanisms by which TRPA1 mediates regulation of thermogenesis at the cellular level. My preliminary data have shown that both mouse and human subcutaneous adipocytes upregulate thermogenic gene expression in response to treatment with the TRPA1 agonists CA and AITC. Additionally, both mouse and human subcutaneous cells upregulate thermogenic gene expression in response to cold exposure. In this aim I will characterize the mechanisms by which TRPA1 agonism upregulates thermogenesis in fat cells by investigating the role that TRPA1 agonism plays in regulating both mitochondrial function and lipolysis. Aim 2: To determine the role that TRPA1 plays in regulating whole-body metabolism. Past studies have shown that inducing thermogenesis in thermogenic fat can counteract obesity and improve glucose metabolism. In this aim I will use mouse models to investigate the role that TRPA1 knockout or agonism has on regulating the thermogenic response to cold and improving glucose metabolism by studying the effects that TRPA1 agonist oral gavage has on regulating thermogenesis in fat tissue and in counteracting high fat diet induced obesity.