ENAMPT-MEDIATED ADIPO-HYPOTHALAMIC COMMUNICATION FOR NAD+ PRODUCTION AND AGING

ENAMPT 介导的脂肪-下丘脑通讯促进 NAD 产生和衰老

• 批准号: 9260757
• 负责人: SHIN-ICHIRO IMAI
• 金额: $ 31.26万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260757
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Age; Aging; Aging-Related Process; Anabolism; Animal Model; Biochemical; Biochemical Reaction; Body Temperature; Brain; Cell Nucleus; Circadian Rhythms; Communication; Complex; Deacetylation; Defect; Development; Energy Metabolism; Enzymes; Equilibrium; Exhibits; Feedback; Female; Functional disorder; Goals; Health; Homeobox; Human; Hypothalamic structure; Immune; Intervention; Knock-in Mouse; Knock-out; Knowledge; Laboratories; Lateral Hypothalamic Nucleus; Life Extension; Longevity; Mammals; Mediating; Mediator of activation protein; Metabolic; Mitochondria; Mus; Neurons; Neurosecretory Systems; Organ; Oxygen Consumption; Pacemakers; Peripheral; Phenotype; Physical activity; Physiological; Play; Production; Proteins; Regulation; Research Proposals; Role; SIRT1 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Sir2-like Deacetylases; Skeletal Muscle; Sleep; Societies; Structure; System; Tissues; Transgenic Mice; Translating; Up-Regulation; age related; effective intervention; extracellular; fly; gain of function; hypocretin; in vivo; insight; male; middle age; mouse model; nicotinamide phosphoribosyltransferase; novel; osmotic minipump; overexpression; polyclonal antibody; prevent; public health relevance; receptor expression; receptor-mediated signaling; relating to nervous system; response; uptake

DESCRIPTION (provided by applicant): Recent studies have suggested that systemic interplay between multiple tissues regulates aging and longevity in model organisms. In mammals, however, the complexity of tissue interplay is multiplied, and a systemic network for mammalian aging/longevity control has been poorly understood. Our long-term goal is to understand such a systemic regulatory network for aging/longevity control in mammals, and to translate that knowledge into an effective intervention to prevent and treat age-associated pathophysiology in humans. To achieve this goal, we have particularly focused on the tissue-specific functions of the mammalian NAD+-dependent protein deacetylase SIRT1, and NAD+ biosynthesis mediated by nicotinamide phosphoribosyltransferase (NAMPT). We have recently demonstrated that the hypothalamus, particularly the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), is the critical place where SIRT1 regulates aging and longevity in mice. Thus, understanding how hypothalamic NAD+ levels are regulated is critical to better understand the system dynamics of mammalian aging/longevity control. Most recently, we have found that adipose tissue plays an important role in modulating NAD+ production in the hypothalamus through the SIRT1-mediated secretion of extracellular NAMPT (eNAMPT). Therefore, we hypothesize that adipose tissue-secreted eNAMPT regulates hypothalamic SIRT1 function, particularly in the DMH and LH, and also that the imbalance between eNAMPT and hypothalamic SIRT1 functions is developed during aging, causing functional defects in the hypothalamus and thereby affecting age-associated pathophysiology in mammals. To address this hypothesis, we will 1) investigate the physiological relevance of eNAMPT in the regulation of hypothalamic SIRT1 function, using loss- and gain-of-function mouse models; 2) confirm the biochemical function of eNAMPT as a systemic NAD+ biosynthetic enzyme by manipulating the equilibrium of the eNAMPT enzymatic reaction in vivo; and 3) assess possible causes for the imbalance between adipose tissue and the hypothalamus during aging by examining changes in eNAMPT enzymatic activity, hypothalamic uptake/utilization of NMN, and SIRT1 protein levels in hypothalamic nuclei, in young, middle age, and old mice. Preliminary results presented in this proposal provide strong support to our hypothesis. Thus, elucidating the physiological importance of this unprecedented intertissue communication mechanism between adipose tissue and the hypothalamus will further advance our understanding of a systemic regulatory network for aging and longevity in mammals and contribute to the development of a possible intervention to achieve better health span in our aging society.

描述（由申请人提供）：最近的研究表明，多个组织之间的全身相互作用调节模型生物的衰老和寿命。然而，在哺乳动物中，组织相互作用的复杂性乘以乘积，并且对哺乳动物衰老/寿命控制的全身网络却鲜为人知。我们的长期目标是了解哺乳动物衰老/寿命控制的系统性调节网络，并将这些知识转化为有效的干预措施，以预防和治疗人类与年龄相关的病理生理学。为了实现这一目标，我们特别关注哺乳动物NAD+依赖性蛋白脱乙酰基酶SIRT1的组织特异性功能，以及由烟酰胺磷酸糖基转移酶（NAMPT）介导的NAD+生物合成。我们最近证明，下丘脑，尤其是背侧和下丘脑外侧核（分别为DMH和LH），是SIRT1调节小鼠衰老和寿命的关键地方。因此，了解下丘脑NAD+水平的调节对于更好地了解哺乳动物衰老/寿命控制的系统动力学至关重要。最近，我们发现脂肪组织通过SIRT1介导的细胞外NAMPT（ENAMPT）的分泌在下丘脑中调节NAD+产生中起重要作用。 Therefore, we hypothesize that adipose tissue-secreted eNAMPT regulates hypothalamic SIRT1 function, particularly in the DMH and LH, and also that the imbalance between eNAMPT and hypothalamic SIRT1 functions is developed during aging, causing functional defects in the hypothalamus and thereby affecting age-associated pathophysiology in mammals.为了解决这一假设，我们将使用功能障碍小鼠模型研究ENAMPT在下丘脑SIRT1功能中的生理相关性； 2）通过在体内操纵ENAMPT酶促反应的平衡来确认ENAMPT作为全身性NAD+生物合成酶的生化功能； 3）评估可能原因是通过检查eNAMPT酶活性的变化，NMN的下丘脑摄取/利用率以及下丘脑核中的SIRT1蛋白水平，在衰老过程中脂肪组织与下丘脑之间的不平衡，年轻人，中年，中年，中年和老鼠。本提案中提出的初步结果为我们的假设提供了强有力的支持。因此，阐明脂肪组织和下丘脑之间这种前所未有的二次间交流机制的生理重要性将进一步促进我们对哺乳动物衰老和寿命的系统性调节网络的理解，并有助于开发可能的干预措施，以实现衰老社会的更好的健康状况。