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，在模式生物中，多种组织之间的系统相互作用调节衰老和寿命。然而，在哺乳动物中，组织相互作用的复杂性成倍增加，而哺乳动物衰老/长寿控制的系统网络一直知之甚少。我们的长期目标是了解哺乳动物衰老/长寿控制的系统调控网络，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依赖的蛋白脱乙酰基酶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。我们最近证实，下丘脑，特别是下丘脑背内侧核和外侧核(分别为DMH和LH)是SIRT1调节小鼠衰老和长寿的关键部位。因此，了解下丘脑NAD水平是如何调节的，对于更好地了解哺乳动物衰老/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的产生中发挥重要作用。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eNAMPT和下丘脑SIRT1功能之间的失衡是在衰老过程中发展起来的，导致下丘脑功能缺陷，从而影响哺乳动物与年龄相关的病理生理学。为了解决这一假说，我们将1)利用功能丧失和获得的小鼠模型探讨eNAMPT在调节下丘脑SIRT1功能中的生理学相关性；2)通过操纵体内eNAMPT酶反应的平衡来确认eNAMPT作为一种系统性NAD生物合成酶的生化功能；以及3)通过检测eNAMPT的酶活性、下丘脑对NMN的摄取/利用和下丘脑核中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的失衡。这一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史无前例的组织间通讯机制的生理意义将进一步促进我们对哺乳动物衰老和长寿的系统调控网络的理解，并有助于开发可能的干预措施，以在我们老龄化的社会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.