Role of Central Neurotensin Signaling in the Ventral Tegmental Area for Ingestive Behavior and Body Weight

中枢神经降压素信号在腹侧被盖区对摄入行为和体重的作用

• 批准号: 10665597
• 负责人: Jariel Yamil Ramirez-Virella
• 金额: $ 4.77万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2025-08-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665597
• 关键词: Agonist; Behavior; Body Weight; Body Weight decreased; Brain; Coupled; Data; Development; Disease; Eating; Energy Metabolism; Feeding behaviors; Fellowship; Food; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Ingestion; Lateral Hypothalamic Area; Learning; Ligand Binding; Measures; Mediating; Motor Activity; Mus; Neurons; Neuropeptides; Neurotensin; Neurotensin Receptors; Obese Mice; Obesity; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physical activity; Population; Psychological reinforcement; Receptor Signaling; Research; Resolution; Rewards; Rodent; Role; Signal Pathway; Signal Transduction; Site; Source; Stress; System; Techniques; Testing; Ventral Tegmental Area; Water consumption; Weight; Weight Gain; Work; antagonist; arm; beta-arrestin; career; combat; dopaminergic neuron; drinking; effective therapy; energy balance; feeding; food consumption; insight; mouse model; natural hypothermia; nervous system disorder; neural; neuromechanism; obesity treatment; optogenetics; pharmacologic; receptor; reduced food intake; restraint; therapy development

Project Summary Overconsumption of food and reduced physical activity cause obesity, but limited understanding of the neuronal systems regulating these behaviors has hindered development of therapies to support weight loss. Intriguingly, injecting the neuropeptide neurotensin (Nts) into the ventral tegmental area (VTA) of the brain suppresses feeding and promotes physical activity, the ideal combination of behaviors for reducing weight. These effects are likely mediated via the subset of dopamine neurons within the VTA that express Neurotensin Receptor-1 (NtsR1) and indeed, activating these neurons in obese mice restrains feeding, increases physical activity, and causes weight loss. Taken together, these data suggest that augmenting Nts-NtsR1 signaling via the VTA may be useful to safely promote weight loss. Here I will test the hypothesis that endogenous or pharmacological enhancement of Nts-NtsR1 signaling will promote weight loss behaviors. In Aim 1 I will augment endogenous Nts input to the VTA. Specifically, I will combine NtsCre mice and optogenetics to activate lateral hypothalamic area neurotensin (LHANts) neurons projecting to the VTA, which have been implicated in promoting weight loss. However, activating all LHANts neurons simultaneously invokes voracious drinking (putatively via projections elsewhere) that mitigates weight loss. My work will reveal if isolating the endogenous LHANts VTA NtsR1 circuit can optimally promote weight loss, without invoking undesirable effects. In Aim 2 I will determine if pharmacological NtsR1 agonists promote weight loss behaviors. NtsR1 is a G-Protein Coupled Receptor that, upon ligand binding to the receptor, can transduce intracellular signaling via Gq-coupled and/or a ß-arrestin pathways, but it remains unclear if one or both of these pathways potentiate weight loss effects. To assess which NtsR1 receptor signaling pathway invokes weight loss, I will administer a general NtsR1 agonist that promotes both Gq-coupled and ß-arrestin signaling or a compound that exclusively activates the ß-arrestin pathway. Agonists will be delivered intra-VTA or systemically to elucidate the brain site and intracellular pathways by which NtsR1 agonism mediates weight loss. Taken together, these data will reveal endogenous and pharmacological mechanisms by which Nts-NtsR1 modulates body weight and may be useful to guide future development of strategies to treat obesity.

项目摘要 过度食用食物和减少体力活动会导致肥胖，但范围有限 对调节这些行为的神经系统的理解阻碍了 支持减肥的疗法。有趣的是，将神经肽神经降压素(NTS)注射到 大脑的腹侧被盖区(VTA)抑制进食和促进体力活动， 减肥行为的理想组合。这些影响很可能是通过 VTA内表达神经降压素受体-1(NtsR1)和 事实上，在肥胖小鼠中激活这些神经元会抑制进食，增加体力活动，并且 会导致体重减轻。综上所述，这些数据表明通过增强NTS-NtsR1信号 VTA对于安全地促进减肥可能是有用的。在这里，我将检验这一假设 NTS-NtsR1信号的内源性或药物增强将促进体重减轻 行为。在目标1中，我将增加内源性NTS对VTA的输入。具体地说，我将结合 NtsCre小鼠与激活下丘脑外侧区神经降压素(LHANts)神经元的光遗传学 预测到VTA，它已经被牵连到促进减肥。但是，激活 所有LHANTS神经元同时引发贪婪的饮酒(可能是通过投射 在其他地方)，这减轻了体重减轻。我的工作将揭示如果分离内源性LHANT VTA NtsR1电路可以最佳地促进减肥，而不会引发不良影响。在AIM 2我将确定药理上的NtsR1激动剂是否促进减肥行为。NtsR1是一种 G蛋白偶联受体，当配体与受体结合时，可以转导细胞内 通过Gq偶联和/或a？arrestin通路传递信号，但目前尚不清楚这两种途径中的一种或两种 这些途径增强了减肥效果。评估哪条NtsR1受体信号通路 为了减肥，我将使用一种通用的NtsR1激动剂，它既能促进GQ偶联，又能促进 ？arrestin信号或专门激活？arrestin途径的化合物。激动剂将 在VTA内或系统内传递，以阐明大脑部位和细胞内通路 哪种NtsR1激动剂能调节体重减轻。综合来看，这些数据将揭示内生性 以及NTS-NtsR1调节体重和可能有用的药理学机制 以指导未来肥胖症治疗策略的发展。