AgRP neurons promote the effects of calorie restriction on lifespan

AgRP 神经元促进热量限制对寿命的影响

• 批准号: 9263491
• 负责人: TAMAS L HORVATH
• 金额: $ 42.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263491
• 关键词: Adipose tissue; Aging; Aging-Related Process; Animals; Autopsy; Behavior; Caloric Restriction; Cells; Cessation of life; Chronology; Deterioration; Generations; Hunger; Hypothalamic structure; Immune system; Impairment; Light; Liver; Longevity; Mediating; Mediator of activation protein; Messenger RNA; Metabolism; Mitochondria; Molecular; Mouse Strains; Mus; Neurons; Pathway interactions; Peptides; Phenotype; Physiology; Process; Production; Role; Structure of beta Cell of islet; System; Testing; Time; Tissues; Transgenic Animals; Transgenic Mice; age effect; bone; carbohydrate metabolism; cohort; lipid metabolism; mRNA Expression; male; muscular system; neuronal circuitry; prevent

Calorie restriction has been show to extend lifespan. A key aspect of calorie restriction is a shift in systemic metabolism from carbohydrate to lipid metabolism. The hypothalamus is a crucial regulator of systemic metabolism and has been directly implicated in the aging process of mice. We uncovered that cell-selective impairment of hypothalamic Agouti-related peptide (AgRP)-expressing neuronal circuitry, part of the hypothalamic melanocortin system, in ad libitum fed mice, results in accelerated aging phenotype of many tissues, including the immune system and bone. We also found that males of mice strains with impaired AgRP neuronal circuitry have shorter mean lifespan when ad libitum fed. Taken together these results gave impetus to the central hypothesis of this proposal, which is that the AgRP system is key mediator in calorie restriction-induced extension of lifespan. We will test our hypothesis through the following specific aims: Specific Aim 1. To test the hypothesis that calorie restriction prevents declining functioning of hypothalamic AgRP neurons in chronological aging. In our preliminary studies we found that AgRP neurons manifest aging associated decline in mitochondrial integrity in ad libitum fed mice. We also observed that calorie restriction promotes AgRP mRNA expression and suppression of POMC mRNA levels. We showed that the input organization of the melanocortin system is shifted by calorie restriction to a constellation that enhances AgRP neuronal activity and suppresses POMC cells. We hypothesize that calorie restriction suppresses deterioration of AgRP neurons during chronological aging, and that this effect is mediated by intracellular pathways regulating mitochondrial dynamics and ROS generation. We will test this hypothesis by analyzing the effect of calorie restriction on AgRP neuronal activity, mitochondrial dynamics and ROS production in control and transgenic mice, in which specific processes of mitochondrial fission, fusion or ROS control is cell-selectively down or up-regulated. Specific Aim 2. To unmask if hypothalamic AgRP neurons are critical for lifespan promotion by calorie restriction. We will utilize multiple lines of transgenic animals in which AgRP neuronal function is selectively up- or down-regulated. Groups of animals will be maintained for lifespan assessment and whole body necropsy will be carried out at the time of death in each. In other control and experimental cohorts, we will analyze the effect of calorie restriction on systemic metabolism and behavior of mice. We will also assess pancreatic beta cell-, adipose-, liver, muscle and immune system parameters of control and experimental animals. The execution of these studies will shad new light on integrative physiology and molecular principles of calorie restriction-induced alterations in heath- and lifespan.

卡路里限制已被证明可以延长寿命。卡路里限制的一个关键方面是系统性的转变 从碳水化合物到脂质代谢的代谢。下丘脑是系统性的关键调节剂 代谢，并直接与小鼠的衰老过程有关。我们发现了细胞选择性 下丘脑Agouti相关肽（AGRP）表达神经元电路的损害， 下丘脑黑色皮质素系统，在自由喂养的小鼠中，导致许多人的衰老表型加速 组织，包括免疫系统和骨骼。我们还发现，AGRP受损的雄性小鼠菌株 自发喂养时，神经元电路的平均寿命较短。总共这些结果给出了 推动该提案的中心假设，即AGRP系统是关键的中介者 卡路里限制诱导的寿命延长。我们将通过以下特定来检验我们的假设 目的：特定目的1。测试卡路里限制阻止功能下降的假设 年代老化的下丘脑AGRP神经元。在我们的初步研究中，我们发现AGRP神经元 明显的衰老相关的衰老下降的线粒体完整性中的小鼠的线粒体完整性。我们还观察到 卡路里限制会促进AGRP mRNA表达和POMC mRNA水平的抑制。我们表明了这一点 黑素皮质素系统的输入组织通过卡路里的限制转移到一个星座上 增强AGRP神经元活性并抑制POMC细胞。我们假设卡路里限制 抑制年代衰老过程中AGRP神经元恶化的恶化，并且这种作用是由 调节线粒体动力学和ROS产生的细胞内途径。我们将通过 分析卡路里限制对AGRP神经元活性，线粒体动力学和ROS的影响 对照和转基因小鼠的产生，其中特定的线粒体裂变，融合或ROS的过程 控制是细胞 - 选择性下调或上调的。具体目的2。揭露下丘脑AGRP神经元是否为 对卡路里限制的寿命至关重要。我们将利用多种转基因动物，其中 AGRP神经元功能被选择性上调或下调。将维持一组动物寿命 评估和全身尸检将在每个人死亡时进行。在其他控制中 实验队列，我们​​将分析卡路里限制对系统性代谢和行为的影响 老鼠。我们还将评估胰腺β细胞，脂肪，肝脏，肌肉和免疫系统参数 控制和实验动物。这些研究的执行将使综合生理学的新启示 卡路里限制诱导的heath和寿命改变的分子原理。