Brainstem LepRb neurons in the control of metabolism

描述（由申请人提供）：肥胖及其代谢后遗症已经成为每年数千亿美元医疗保健支出的基础，肥胖的发病率是 预计在未来15年内将上升到40%。因此，了解控制能量平衡和代谢的机制的需求变得越来越迫切，因为这些知识对于确定致病机制和开发新疗法至关重要。瘦素是一种与脂肪能量储存成比例分泌的脂肪细胞来源的激素，通过其受体（LepRb）的长同种型在中枢神经系统中起作用以控制行为（例如，喂养）和生理学（例如，葡萄糖稳态）与能量平衡有关。瘦素在控制能量稳态中所起的核心作用表明了解瘦素介导其作用的机制的重要性。 瘦素反应（表达LepRb）神经元位于许多对控制代谢功能至关重要的脑区域，包括下丘脑中基底核（MBH）核（例如，弓状核（ARC））和脑干。虽然MBH瘦素作用是重要的，近年来受到了相当大的关注，但MBH瘦素信号传导只能解释瘦素作用的一小部分。脑干含有许多不同的LepRb神经元群体;中脑导水管周围灰质（PAG）和臂旁外侧核（IPBN）含有最大的脑干LepRb神经元群体（与主要下丘脑核中的LepRb群体相当）。虽然这两个核团都有助于控制饱腹感和自主神经功能，但LepRb神经元在这些区域中的作用仍然未知。我们发现许多PAG/lPBN LepRb神经元含有神经肽胆囊收缩素（CCK），并且这些LepRbCCK神经元的分布仅限于脑干。此外，我们的初步数据揭示了这些神经元在控制食物摄入、体重和葡萄糖依赖性反应中的作用。在这个提议中，我们将采用一组分子遗传工具来定义脑干LepRb神经元的调节和连接。此外，我们将操纵这些神经元的活动，以及它们对瘦素的反应，以确定它们的神经和生理功能。这些研究将为深入了解瘦素在中枢神经系统中的作用机制以及能量和葡萄糖稳态的控制提供重要的线索。

DESCRIPTION (provided by applicant): Obesity and its metabolic sequelae already underlie hundreds of billions of dollars in annual health care expenditures, and the incidence of obesity is projected to rise to 40% within the next fifteen years. The need to understand the mechanisms controlling energy balance and metabolism thus continues to grow ever more pressing, since this knowledge will be crucial for defining pathogenic mechanisms and for the development of novel therapies. Leptin, an adipocyte-derived hormone secreted in proportion to adipose energy stores, acts via the long isoform of its receptor (LepRb) in the central nervous system to control behavior (e.g., feeding) and physiology (e.g., glucose homeostasis) relevant to energy balance. The central role played by leptin in the control of energy homeostasis suggests the importance of understanding the mechanisms by which leptin mediates its effects. Leptin-responsive (LepRb-expressing) neurons lie in a number of brain regions crucial for the control of metabolic function, including mediobasal hypothalamic (MBH) nuclei (e.g., arcuate nucleus (ARC)) and the brainstem. While MBH leptin action is important and has received considerable attention in recent years, MBH leptin signaling can only account for a fraction of leptin action. The brainstem contains a number of distinct populations of LepRb neurons; the periaqueductal grey (PAG) and lateral parabrachial (lPBN) nuclei contain the largest groups of brainstem LepRb neurons (comparable to LepRb populations in major hypothalamic nuclei). While both of these nuclei contribute to the control of satiety and autonomic function, the roles for LepRb neurons in these regions remain unknown. We found that many PAG/lPBN LepRb neurons contain the neuropeptide, cholecystokinin (CCK), and that the distribution of these LepRbCCK neurons is restricted to the brainstem. Furthermore, our preliminary data reveal roles for these neurons in the control of food intake, body weight, and the glucoprivic response. In this proposal, we will employ a panel of molecular genetic tools to define the regulation and connectivity of brainstem LepRb neurons. Furthermore, we will manipulate the activity of these neurons, as well as their responsiveness to leptin, in order to define their neural and physiologic functions. These studies will provide important insights into novel mechanisms of leptin action in the central nervous system and into the control of energy and glucose homeostasis.