Grhelin, NPY/Agrp Neurons, and Meal Initiation

体重调节涉及食物摄入量的调整，以补偿能量储备的波动。这些调整包括进餐数量、体型或两者兼而有之。与众所周知的控制用餐终止从而控制用餐大小的系统相比，那些控制用餐开始和频率的系统仍然是谜。 最近发现的胃肠激素Ghrelin与一系列导致进食的事件有关，但支持这一断言的证据在很大程度上是间接的。我们建议使用功能丧失实验，在进食起始中严格测试对Ghrelin及其最成熟的中枢神经系统靶点-NPY/AgRP神经元的需求。我们将解决以下广泛的问题。(1)正常进餐开始、终止进餐或两者兼而有之是否需要Ghrelin信号？使用最先进的设备以秒到秒的速度连续测量食物摄入量 在此基础上，我们将评估新的、高效的Ghrelin受体拮抗剂(GHS-R)在减少总体食物摄入量的剂量下对进餐次数、大小和持续时间的影响。实验将在随意喂养的小鼠以及那些受到各种急性和慢性能量缺乏状态的小鼠身上进行，这些状态挑战了进食开始的信号。 我们将对野生型和GHS-R/-小鼠进行平行研究，以验证GHS-R拮抗剂的厌食效应是由于阻断GHS-R而产生的，也是为了比较互补的药理学和遗传消融对GHS-R信号的影响。(2)NPY/AgRP神经元是正常进食起始、能量平衡和对Ghrelin反应所必需的吗？我们的合作者格雷格·巴什博士已经创造了NPY/AgRP的小鼠 神经元在成年期被逐渐和持续地破坏。这些动物是一个有价值的资源，可以确定在Ghrelin的每一种已知合成代谢活动中对NPY/AgRP神经元的需求，以及评估NPY/AgRP神经元本身在进食模式和总体能量平衡中的作用。我们建议对这些小鼠进行彻底的表型分析来解决这些问题。(3)Ghrelin触发的细胞内信号事件在 下丘脑的关键神经元--特别是NPY/AgRP神经元--反对由瘦素和胰岛素触发的神经元(反之亦然)？总之，这些研究有可能从根本上促进我们在分子、细胞和行为水平上对摄食生物学的理解。

Body weight regulation involves adjustments in food intake that compensate for fluctuations in energy stores. These adjustments are comprised of alterations in meal number, size, or both. Compared with the well understood systems that regulate meal termination, and thus, meal size, those that regulate meal initiation and frequency remain enigmatic. The recently discovered enteric hormone, ghrelin, is implicated in the cascade of events leading to meal initiation, but evidence favoring this assertion is largely circumstantial. We propose to test critically the requirement for ghrelin and its most well established CNS target - NPY/Agrp neurons - in meal initiation, using loss-of-function experiments. We will address the following broad questions. (1) Is ghrelin signaling required for normal meal initiation, meal termination, or both? Using state-of-the art equipment to measure food intake continuously on a second-to-second basis, we will assess the effect on meal number, size, and duration, of novel, highly potent antagonists of the ghrelin receptor (GHS-R), at doses that decrease overall food intake. Experiments will be conducted on ad libitum-fed mice as well as those subjected to a variety of acute and chronic states of energy deficit that challenge meal-initiation signals. We will study wild-type and GHS-R /- mice in parallel, both to verify that the anorectic effects of GHS-R antagonists result specifically from blockade of the GHS-R, and also to compare the effects of complementary pharmacologic and genetic ablation of GHS-R signaling. (2) Are NPY/Agrp neurons required for normal meal initiation, energy homeostasis, and response to ghrelin? Our co-investigator, Dr. Greg Barsh, has created mice in which NPY/Agrp neurons are gradually and continuously destroyed in adulthood. The animals are a valuable resource to determine the requirement for NPY/Agrp neurons in each of ghrelin's known anabolic actions, as well as to assess the role of NPY/Agrp neurons themselves in meal patterning and overall energy homeostasis. We propose a thorough phenotyping analysis of these mice to address these issues. (3) Do intracellular signaling events triggered by ghrelin in key hypothalamic neurons - especially NPY/Agrp neurons - oppose those triggered by leptin and insulin (and vice versa)? Together, these studies have the potential to fundamentally advance our understanding of feeding biology at the molecular, cellular, and behavioral level.