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

项目摘要 过度消费食物和减少体力活动导致肥胖，但有限 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）抑制进食并促进身体活动， 减肥行为的理想组合。这些影响可能是通过 VTA内表达神经降压素受体-1（NtsR 1）的多巴胺神经元亚群， 事实上，激活肥胖小鼠的这些神经元可以抑制进食，增加体力活动， 导致体重减轻。综上所述，这些数据表明，通过增强Nts-NtsR 1信号传导， VTA可用于安全地促进体重减轻。在这里，我将检验这样的假设： Nts-NtsR 1信号传导的内源性或药理学增强将促进体重减轻 行为。在目标1中，我将增加VTA的内源性Nts输入。具体来说，我将联合收割机 NtsCre小鼠和光遗传学激活外侧下丘脑区神经降压素（LHANts）神经元 投射到腹侧被盖区，这与促进减肥有关。然而，激活 所有的LHANts神经元同时引起贪婪的饮酒（通过投射 其他地方），减轻体重减轻。我的工作将揭示如果分离内源性LHANts， VTA NtsR 1电路可以最佳地促进减肥，而不会引起不良影响。在Aim中 2我将确定药物NtsR 1激动剂是否促进减肥行为。NtsR 1是一个 G蛋白偶联受体，在配体与受体结合后，可在细胞内激活 通过Gq-偶联和/或α-抑制蛋白途径进行信号传导，但仍不清楚是否存在以下一种或两种情况： 这些途径增强了减肥效果。为了评估NtsR 1受体信号通路 调用减肥，我将管理一个通用的NtsR 1激动剂，促进Gq耦合， β-抑制蛋白信号传导或专门激活β-抑制蛋白途径的化合物。激动剂将 VTA内或全身给药，以阐明脑部位和细胞内途径， NtsR 1激动介导体重减轻。综合来看，这些数据将揭示内生性 以及Nts-NtsR 1调节体重的药理学机制， 以指导未来治疗肥胖症的策略的发展。

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.