Neural mechanisms in high fat diet impairment of brown adipose tissue activity

项目摘要 棕色脂肪组织(BAT)的交感神经激活增加了 这种组织中的脂肪酸。由于解偶联蛋白-1存在于猪的线粒体中 由电子传输链产生的电化学梯度在 缺乏三磷酸腺苷的生产。这一过程是BAT独有的(也是可诱导的 蝙蝠的形式，“米色”脂肪组织)在本质上代谢脂肪产生热量。显而易见的事情 这种“脂肪燃烧”过程对能量平衡和体重调节的影响导致 对控制这一过程的生物机制产生了浓厚的兴趣。该组织的活动 支配蝙蝠的交感神经是这一过程的主要调节器。我们的研究已经 明确了热刺激和热刺激引起的基本神经通路 变化在交感神经流出到蝙蝠。然而，人们对神经的了解相对较少。 参与代谢的回路对蝙蝠的影响以及饮食成分(如 饮食中的脂肪含量)影响这些调节回路。 在拟议的研究项目中，我们将在体内和体内进行一系列广泛的 体外电生理学、解剖学、神经药理学和设计型受体 由设计药物(DREADD)实验独家激活，以解决特定目标 将为BAT损伤的神经机制提供新的见解 高脂饮食(HFD)时的激活以及这种损害对HFD的具体贡献 诱导体重增加。第一个目的将确定瞬时受体电位香草素的作用。 NTS中的1型(TRPV1)在高脂肪维持期间BAT激活的损害 节食。第二个目标将确定负责的NTS的下游预测目标 用于在HFD期间抑制对BAT的交感神经输出。第三个目标将定义 臂旁外侧核强啡肽前神经元与kappa阿片受体 在HFD期间，视前区的激活对BAT激活的损害。第四个目标将 确定kappa阿片类药物的输出投射靶点和神经生理特性 视前区含有受体的神经元。

Project Summary The sympathetic activation of brown adipose tissue (BAT) increases the metabolism of fatty acids within this tissue. Due to the presence of uncoupling protein-1 in the mitochondria of BAT the electrochemical gradient generated by the electron transport chain is dissipated in the absence of the production of ATP. This process which is unique to BAT (as well as inducible forms of BAT, “beige” adipose tissue) in essence metabolizes fat to produce heat. The obvious implications of this “fat burning” process for energy balance and body weight regulation have led to intense interest in the biological mechanisms governing this process. The activity of the sympathetic nerves innervating BAT is the principal regulator of this process. Our research has defined the fundamental neural pathways through which thermal and febrile stimuli elicit changes in the sympathetic outflow to BAT. However, relatively little is known about the neural circuits involved in the metabolic influences on BAT and how dietary components (such as the fat content of the diet) influence these regulatory circuits. In the proposed research project, we will perform an extensive series of in vivo and in vitro electrophysiological, anatomical, neuropharmacological, and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) experiments to address specific aims that will provide new insights into the neural mechanisms responsible for the impairment of BAT activation during high fat diet (HFD) and the specific contribution of this impairment to HFD- induced weight gain. The first aim will determine the role of transient receptor potential vanilloid type 1 (TRPV1) in NTS in the impairment of BAT activation during maintenance on a high fat diet. The second aim will define the downstream projection target of the NTS that is responsible for inhibition of sympathetic output to BAT during HFD. The third aim will define the role of preprodynorphin neurons in the lateral parabrachial nucleus and kappa opioid receptor activation in the preoptic area in the impairment of BAT activation during HFD. The forth aim will define the output projection target and neurophysiological characteristics of kappa opioid receptor containing neurons of the preoptic area.