Role of GDF15 and its receptor in the CNS regulation of food intake and body weight

GDF15及其受体在中枢神经系统食物摄入和体重调节中的作用

• 批准号: 10311051
• 负责人: RANDY J SEELEY
• 金额: $ 46.56万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311051
• 关键词: Adult; Affinity; Agonist; Anorexia; Appetite Depressants; Area; Axon; Behavior Therapy; Biology; Blood - brain barrier anatomy; Body Weight; Body Weight decreased; Brain Stem; Categories; Cell Nucleus; Chronic; Data; Desire for food; Dose; Eating; Family; Fatty acid glycerol esters; Food; Food Energy; Food Intake Regulation; GDF15 gene; Healthcare Systems; High Fat Diet; Human; Hypothalamic structure; Individual; Infection; Infusion procedures; Label; Lead; Link; Malignant Neoplasms; Mediating; Medical; Molecular Genetics; Mus; Neurons; Obesity; Organ; Paper; Peptides; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Physiological; Placebos; Play; Population; Positioning Attribute; Publications; Publishing; Regulation; Research; Rodent; Role; Series; Signal Transduction; Site; Societies; Stimulus; Structure of area postrema; Structure of nucleus infundibularis hypothalami; System; Techniques; Testing; Tetanus Toxin; Therapeutic; Tracer; Transforming Growth Factor beta; Viral; Weight Gain; Work; analog; anorexic; bariatric surgery; cost; designer receptors exclusively activated by designer drugs; effective therapy; energy balance; feeding; glial cell-line derived neurotrophic factor; hindbrain; islet amyloid polypeptide; member; mouse model; neurochemistry; neuromechanism; neuronal cell body; nonhuman primate; novel; obese person; obesity treatment; programs; receptor; reduced food intake; response; tool; treatment strategy; tumor

Project Summary/Abstract Obesity remains one of the largest unmet medical needs facing the US healthcare system. More than one in three adults in the US are obese and these rates continue to increase with the most severe category of obesity unfortunately growing the fastest. It is hard to overstate the human and monetary costs to the individuals impacted and society as a whole. It remains that very few of these individuals receive effective therapies. The existing behavioral interventions have limited efficacy. While the approved pharmacological therapies are more successful, none of the currently approved therapies produce even 10% sustained body weight loss on a placebo-adjusted basis. Consequently, there is still an enormous need for additional pharmacological treatments for individuals with obesity. Growth differentiation factor 15 is a member of the TGFβ superfamily that has been linked to the anorexia and weight loss that occurs with some cancers. This launched a number of programs to harness GDF15 analogues as obesity therapeutics and to identify the receptor that mediates these effects. Such efforts culminated in a series of 4 high-profile papers published in late 2017 that each identified GDNF family receptor α-like (GFRAL) as a high affinity receptor for GDF15 and is absolutely required for the potent effects of GDF15 to reduce food intake and body weight. Interestingly, GFRAL is almost exclusively expressed in the CNS. Moreover, its distribution in the CNS is almost entirely limited to a brainstem area termed the area postrema which sits outside the blood-brain barrier. Given the powerful weight loss effects of GDF15 mediated by this small population of neurons, it points to a very important role of these neurons to regulate food intake and energy balance. We have built state-of-the-art mouse models that will allow us to selectively identify, track and manipulate these neurons. To that end, we will identify the projections from these neurons both within the caudal portion of the brainstem and to hypothalamic areas that have been linked to the regulation of body weight. We will also use these tools to selectively activate or silence these neurons and assess their role in normal control of energy balance and to mediate the effects of other weight loss manipulations. This work has enormous significance and novelty. GDF15 is one of the most promising new treatment strategies for obese individuals. Maybe even more importantly, the potent effects of GDF15 point to a novel CNS circuit engaged from a very small population of neurons located in the area postrema. Establishing components of this circuit and key aspects of GDF15 biology will maximize the potential utility of GDF15 as a therapeutic and identify new targets that target key components of this system.

项目总结/摘要 肥胖仍然是美国医疗保健系统面临的最大未满足的医疗需求之一。多于一 在美国，三分之一的成年人肥胖，这些比率继续增加， 不幸的是肥胖症增长最快。这是很难夸大的人力和财力成本， 个人和整个社会都受到影响。然而，这些人中很少有人能有效地 治疗现有的行为干预措施效果有限。虽然批准的药理学 目前批准的治疗方法中，没有一种能产生10%的持续体质量。 在安慰剂调整的基础上减轻体重。因此，仍然需要大量增加 用于肥胖个体的药物治疗。 生长分化因子15是TGFβ超家族的一员，与厌食症有关。 以及某些癌症患者的体重减轻。这启动了许多利用GDF 15的计划 类似物作为肥胖治疗剂，并鉴定介导这些作用的受体。这种努力 最终在2017年底发表了一系列4篇备受瞩目的论文，每篇论文都确定了GDNF家族受体 α-样（GFRAL）作为GDF 15的高亲和力受体，并且是GDF 15的强效作用所绝对需要的 减少食物摄入量和体重。有趣的是，GFRAL几乎仅在CNS中表达。 此外，它在CNS中的分布几乎完全限于脑干区域，称为最后区 位于血脑屏障之外 考虑到GDF 15由这一小部分神经元介导的强大的减肥作用，它指出了一种新的减肥方法。 这些神经元在调节食物摄入和能量平衡方面起着非常重要的作用。我们建造了最先进的 小鼠模型，这将使我们能够选择性地识别，跟踪和操纵这些神经元。为此我们 将识别这些神经元的投射，这些神经元既位于脑干的尾部， 下丘脑区域与体重调节有关。我们还将使用这些工具， 选择性地激活或沉默这些神经元，并评估它们在正常控制能量平衡中的作用， 调节其他减肥方法的效果。这项工作具有巨大的意义和新奇。 GDF 15是肥胖患者最有前途的新治疗策略之一。也许更 重要的是，GDF 15的有效作用指向一种新的CNS回路， 位于最后区的神经元。建立该电路的组件和GDF 15的关键方面 生物学将最大限度地发挥GDF 15作为治疗药物的潜在效用，并确定新的靶点， 这个系统的组成部分。