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

描述（由申请人提供）：最近的研究表明，多种组织之间的系统性相互作用调节着模式生物的衰老和寿命。然而，在哺乳动物中，组织相互作用的复杂性成倍增加，并且对哺乳动物衰老/长寿控制的系统网络知之甚少。我们的长期目标是了解哺乳动物衰老/寿命控制的系统调节网络，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。为了实现这一目标，我们特别关注哺乳动物NAD+依赖蛋白去乙酰化酶SIRT1的组织特异性功能，以及烟酰胺磷酸核糖基转移酶（NAMPT）介导的NAD+生物合成。我们最近证明，下丘脑，特别是背内侧和外侧下丘脑核（分别为DMH和LH），是SIRT1调节小鼠衰老和寿命的关键部位。因此，了解下丘脑NAD+水平是如何调控的对于更好地理解哺乳动物衰老/长寿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，在调节下丘脑NAD+的产生中起重要作用。因此，我们假设脂肪组织分泌的eNAMPT调节下丘脑SIRT1功能，特别是在DMH和LH中，并且在衰老过程中形成了eNAMPT与下丘脑SIRT1功能之间的不平衡，导致下丘脑功能缺陷，从而影响哺乳动物年龄相关的病理生理。为了解决这一假设，我们将1)研究eNAMPT在调节下丘脑SIRT1功能中的生理相关性，使用功能丧失和功能获得小鼠模型；2)通过调节体内eNAMPT酶促反应的平衡，证实了eNAMPT作为系统性NAD+生物合成酶的生化功能；3)通过检测年轻、中年和老年小鼠中eNAMPT酶活性、下丘脑对NMN的摄取/利用以及下丘脑核中SIRT1蛋白水平的变化，评估衰老过程中脂肪组织和下丘脑之间失衡的可能原因。本提案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组织间通讯机制的生理重要性，将进一步促进我们对哺乳动物衰老和长寿的系统性调节网络的理解，并有助于开发可能的干预措施，以在我们的老龄化社会中实现更好的健康寿命。

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.