Regulation of Thermogenesis in Adipocytes Through TRPA1

项目摘要 肥胖是一种全球流行病，与许多破坏性疾病有关，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了解这些疾病和 确定预防它们的可能策略。生热脂肪细胞是一种脂肪细胞，它能上调 对冷刺激作出反应的产热程序。产热程序的这种上调导致了 脂肪细胞以热量的形式分散能量，而不是储存能量。生热脂肪细胞最近已经被 在成人中发现，研究表明，人类活跃的生热脂肪细胞是 与改善的代谢参数相关，表明这些细胞是糖尿病的有希望的靶点 还有肥胖症治疗。我的初步数据显示，使用瞬时受体治疗脂肪细胞 潜在阳离子通道A1(TRPA1)激动剂肉桂醛(CA)和异硫氰酸烯丙酯(AITC)增加 致热基因的表达。我假设TRPA1介导脂肪细胞的生热反应，并 TRPA1激动剂将提高耐寒性并对抗肥胖。我建议研究生热作用-- 小鼠和人的生热脂肪细胞对TRPA1激活的相关变化和 TRPA1激动剂或基因敲除对体内产热和糖代谢的调节作用。 目的1：研究TRPA1介导的生热调节机制。 细胞水平。我的初步数据显示，小鼠和人类的皮下脂肪细胞 对TRPA1激动剂CA和AITC的治疗反应上调致热基因的表达。 此外，小鼠和人类的皮下细胞都上调了产热基因的表达。 暴露在寒冷的环境中。在这个目标中，我将描述TRPA1激动剂上调的机制 通过研究TRPA1激动剂在调节两种线粒体中的作用来研究脂肪细胞的生热作用 功能和脂解作用。 目的2：确定TRPA1在调节全身代谢中的作用。过去的研究表明 研究表明，在生热脂肪中诱导产热可以抵消肥胖和改善血糖。 新陈代谢。为了达到这个目的，我将使用小鼠模型来研究TRPA1基因敲除或激动症所起的作用 从研究丹参对生热反应和改善糖代谢的作用谈 TRPA1激动剂口服对脂肪组织产热的调节和对高脂饮食的对抗作用 诱导性肥胖。

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.