The Intracellular Dynamics of AGRP Neurons under Different Metabolic Conditions

不同代谢条件下 AGRP 神经元的细胞内动力学

• 批准号: 9769009
• 负责人: Marcelo Dietrich
• 金额: $ 37.46万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769009
• 关键词: Acute; Animals; Applications Grants; Biology; Cells; Chronic; Diabetes Mellitus; Diet; Disease; Drug Targeting; Electrons; Energy Metabolism; Etiology; Fatty acid glycerol esters; Food deprivation (experimental); Functional disorder; Goals; High Fat Diet; Human; Hunger; Hypothalamic structure; Impairment; Lead; Life; Maintenance; Mediating; Metabolic; Metabolic Diseases; Metabolism; Microscopic; Mitochondria; Morphology; Mus; Neurons; Obese Mice; Obesity; Organism; Pathway interactions; Recombinant adeno-associated virus (rAAV); Regulation; Resistance; Ribosomes; Rodent; Role; Time; Transgenic Organisms; design; energy balance; experimental study; feeding; fighting; insight; knock-down; mouse model; novel; public health relevance; response; ribosome profiling; transcriptome; transcriptome sequencing; translatome

 DESCRIPTION (provided by applicant): The maintenance of energy metabolism is a fundamental homeostatic function found in all organisms from humans to simple cells. Disruption of energy metabolism can lead to life-threatening conditions, including chronic metabolic disorders such as obesity and diabetes. Understanding the regulatory principles that control energy metabolism is of the utmost importance in helping to design better treatments for metabolic disorders. AGRP neurons in the hypothalamus participate in the regulation of energy metabolism and are activated during times of food deprivation. Paradoxically, we showed that AGRP neuronal activity is also elevated in diet- induced obese mice. We have recently found that mitochondria in AGRP neurons undergo fusion when mice switch from negative to positive energy balance (i.e., from food deprived to high-fat fed). When we blocked mitochondria fusion in AGRP neurons (by knocking down Mfn2) in mice fed a high-fat diet, AGRP neuron activity decreased due to reduced intracellular levels of ATP, and the mice became resistant to diet-induced obesity. Because in both food deprived and high-fat diet fed mice the activity of AGRP neurons is high, we hypothesize that AGRP neuron activity is supported by different mechanisms in these two conditions. This is illustrated by the fission state of mitochondria in AGRP neurons during food deprivation, and the fused state in high-fat fed mice. The goal of this application is to provide mechanistic insight into the complexity of the biology involved in the adaptations of AGRP neurons to different metabolic conditions. In Aim 1, we will use cell-specific ribosome profiling of AGRP neurons combined with RNA-sequencing to identify changes in the translational landscape of AGRP neurons. In Sub-Aim 1.1 we will characterize the ribosome-associated transcriptome (translatome) involved in AGRP neuron function in food deprived, fed and high-fat diet fed mice. In Sub-Aim 1.2 we will characterize how the translatome of AGRP neurons is modified in the absence of mitochondria fusion during diet-induced obesity in AGRP-Mfn2KO mice. These experiments will identify the putative intracellular mechanisms that allow AGRP neurons to adapt to the changing metabolic milieu. In Aim 2, we will tackle a very important mechanistic question that is whether mitochondrial dynamics in AGRP neurons is controlled by the electrical activity of the cells. We will use a multi-faceted approach to selectively and acutely activate/inhibit Agrp neurons utilizing transgenic and AAV-mediated mouse models with the goal of identifying dynamic morphological changes in mitochondria through electron microscopic analyses. This proposal will deliver novel insights into the central regulation of metabolism and offer new candidates to pursue as drug targets for obesity and related metabolic disorders.

 描述（由申请人提供）：能量代谢的维持是从人类到简单细胞的所有生物体中发现的基本稳态功能。能量代谢的破坏可能导致危及生命的疾病，包括肥胖和糖尿病等慢性代谢性疾病。控制能量代谢的调节原则对于帮助设计更好的代谢紊乱治疗方法至关重要，下丘脑中的 AGRP 神经元参与能量代谢的调节，并且在食物匮乏时被激活。在饮食诱导的肥胖小鼠中，AGRP 神经元活性也会升高。我们最近发现，当小鼠从负能量平衡转变为正能量平衡时（即，当我们阻断线粒体时，从食物匮乏到高脂肪喂养），AGRP 神经元中的线粒体会发生融合。在喂食高脂肪饮食的小鼠中，AGRP 神经元发生融合（通过敲低 Mfn2），由于细胞内 ATP 水平降低，AGRP 神经元活性降低，并且小鼠对饮食诱导的肥胖产生了抵抗力。在食物匮乏和高脂肪饮食喂养的小鼠中，AGRP 神经元的活性很高，我们发现在这两种条件下，AGRP 神经元的活性是由不同的机制支持的，这可以通过食物匮乏期间 AGRP 神经元中线粒体的裂变状态来说明。该应用的目的是提供有关 AGRP 神经元适应不同代谢条件的生物学复杂性的机制。通过 RNA 测序对组合 AGRP 神经元进行分析，以确定 AGRP 神经元翻译景观的变化。在 Sub-Aim 1.1 中，我们将描述在食物匮乏、进食和高脂肪情况下参与 AGRP 神经元功能的核糖体相关转录组（翻译组）。在 Sub-Aim 1.2 中，我们将描述 AGRP-Mfn2KO 中饮食诱导的肥胖期间 AGRP 神经元的翻译组在缺乏线粒体融合的情况下如何被修饰。这些实验将确定允许 AGRP 神经元适应不断变化的代谢环境的假定细胞内机制。在目标 2 中，我们将解决一个非常重要的机制问题，即 AGRP 神经元中的线粒体动力学是否受控于 AGRP 神经元的电活动。我们将采用多方面的方法，利用转基因和 AAV 介导的小鼠模型来选择性地、急性地激活/抑制 Agrp 神经元，目的是通过电子显微镜分析来识别线粒体的动态形态变化。对代谢中央调节的新见解，并提供新的候选药物作为肥胖和相关代谢紊乱的药物靶点。

项目成果

AgRP neurons control compulsive exercise and survival in an activity-based anorexia model.

AgRP 神经元在基于活动的厌食症模型中控制强迫运动和生存。

• 发表时间: 2020
• 影响因子: 20.8
• 作者: Miletta, Maria Consolata;Iyilikci, Onur;Shanabrough, Marya;Šestan;Cammisa, Allison;Zeiss, Caroline J;Dietrich, Marcelo O;Horvath, Tamas L
• 通讯作者: Horvath, Tamas L

Development of "Hunger Neurons" and the Unanticipated Relationship Between Energy Metabolism and Mother-Infant Interactions.

“饥饿神经元”的发展以及能量代谢与母婴互动之间意想不到的关系。

• 发表时间: 2022-05-15
• 影响因子: 10.6
• 作者: Iyilikci, Onur;Zimmer, Marcelo R;Dietrich, Marcelo O
• 通讯作者: Dietrich, Marcelo O

Activation of Agrp neurons modulates memory-related cognitive processes in mice.

Agrp 神经元的激活调节小鼠记忆相关的认知过程。

• 发表时间: 2019
• 影响因子: 9.3
• 作者: Zimmer, Marcelo R;Schmitz, Ariana E;Dietrich, Marcelo O
• 通讯作者: Dietrich, Marcelo O