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.

热量限制已被证明可以延长寿命。热量限制的一个关键方面是系统性的转变， 从碳水化合物代谢到脂质代谢。下丘脑是一个重要的调节器， 代谢，并直接参与小鼠的衰老过程。我们发现细胞选择性 下丘脑Agouti-related peptide（AgRP）表达神经元回路的损伤， 自由采食小鼠的下丘脑黑皮质素系统导致许多人的加速衰老表型， 组织，包括免疫系统和骨骼。我们还发现AgRP受损的雄性小鼠 当随意进食时，神经元回路具有较短的平均寿命。综合这些结果， 这一建议的中心假设的动力，这是AgRP系统是关键调解人， 热量限制导致的寿命延长。我们将通过以下具体步骤来检验我们的假设： 目标：具体目标1.为了验证限制卡路里摄入可以防止大脑功能下降的假设， 下丘脑AgRP神经元随年龄增长的变化。在我们的初步研究中，我们发现AgRP神经元 在随意喂养的小鼠中表现出衰老相关的线粒体完整性下降。我们还观察到 热量限制促进AgRP mRNA表达和抑制POMC mRNA水平。我们发现 黑皮质素系统的输入组织通过卡路里限制而转移到 增强AgRP神经元活性并抑制POMC细胞。我们假设限制卡路里摄入 抑制AgRP神经元在时间老化过程中的退化，这种作用是由 调节线粒体动力学和ROS产生的细胞内途径。我们将通过以下方式检验这一假设： 分析热量限制对AgRP神经元活性、线粒体动力学和ROS的影响 在对照和转基因小鼠中的生产，其中线粒体分裂，融合或ROS的特定过程 控制是细胞选择性下调或上调的。具体目标2。为了揭示下丘脑AgRP神经元是否 这对通过限制卡路里来延长寿命至关重要。我们将利用多个转基因动物品系， AgRP神经元功能选择性上调或下调。动物组将在整个生命周期内维持 将在每只动物死亡时进行评估和全身尸检。在其他控制和 实验队列，我们将分析热量限制对全身代谢和行为的影响， 小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。这些研究的实施将为整合生理学提供新的视角 以及热量限制引起的健康和寿命变化的分子原理。