Impact of Sex and Diet on Mesolimbic Amylin Signaling for Energy Balance Control

项目总结/摘要 肥胖症是一种非常普遍和昂贵的疾病，但有效和非侵入性的治疗选择， 严格限制。胰淀素系统被认为是开发新型抗肿瘤药物的有希望的候选者。 肥胖症药物疗法，如胰淀素激动剂，减少人类的食物摄入并产生体重减轻， 动物模型腹侧被盖区（VTA）是一个在摄食和发育中起关键作用的中脑边缘核， 动机行为，是能量平衡的生理和心理相关的作用部位 amylin的作用然而，VTA胰淀素受体介导的食欲减退的机制仍然存在， 悬而未决特别是，性别和饮食等关键变量对VTA胰淀素受体能力的影响 激活以促进负能量平衡尚不清楚。本提案的总体目标是 VTA胰淀素受体信号传导新神经解剖学和行为机制的鉴定 促进食欲减退和体重减轻，特别关注性别和饮食在这些影响中的作用。 该奖项将通过以下方式促进申请人成为完全独立的PI 探索中脑边缘胰淀素信号转导的新课题，并为一个新的研究项目提供关键的初步数据。 未来的R 01应用。具体目标I使用病毒遗传学和行为学的创新组合， 药理学测试是否VTA投射神经元的刺激在外侧下丘脑，中枢 胰淀素的来源，激活腹侧被盖区胰淀素受体以控制能量平衡。这将扩大我们的知识， 研究VTA胰淀素受体的输入，并将通过测试提供对性别和饮食差异的了解。 雄性和雌性大鼠维持食物或高脂肪饮食（HFD）。具体目标II评估生理 VTA胰淀素受体与雌性动物长期能量平衡控制的相关性， VTA胰淀素受体敲低的体重效应。该目的还检查VTA胰淀素的表型 受体表达细胞在女性的免疫组织化学和原位杂交相结合。的 本申请中描述的研究是在申请人目前获得的K 01奖的基础上，通过调查神经系统， VTA胰淀素受体信号传导控制能量平衡的电路和行为机制， 解决饮食影响（例如，可口的HFD或清淡的食物）。这些研究 通过探索一个新颖而重要的主题：性别差异的作用， 在中脑边缘胰淀素信号传导中。这些研究的目的是产生翔实的数据， R 01应用程序中要解决的后续问题的生成起点。新组合 在拟议的研究中使用的体内和离体技术将进一步我们对分布式的理解。 胰淀素在大脑中控制能量平衡的作用，填补了我们科学知识的重要空白， 可以进一步开发用于治疗肥胖症的新的基于胰淀素的药物疗法。

Project Summary/Abstract Obesity is a highly prevalent and costly disease, but effective and non-invasive treatment options are severely limited. The amylin system is considered a promising candidate for the development of novel anti- obesity pharmacotherapies, as amylin agonists decrease food intake and produce weight loss in humans and animal models. The ventral tegmental area (VTA), a mesolimbic nucleus with critical roles in feeding and motivated behavior, is a physiologically and pharmacologically relevant site of action for the energy balance effects of amylin. However, the mechanisms underlying VTA amylin receptor-mediated hypophagia remain unresolved. In particular, the impacts of key variables like sex and diet on the ability of VTA amylin receptor activation to promote negative energy balance are unknown. The overarching goal of this proposal is to identify novel neuroanatomical and behavioral mechanisms by which VTA amylin receptor signaling promotes hypophagia and weight loss, with particular focus on the role of sex and diet in these effects. This award will facilitate the applicant's advancement toward becoming a fully independent PI by exploring new topics in mesolimbic amylin signaling and generating crucial preliminary data for a future R01 application. Specific Aim I uses an innovative combination of virogenetics and behavioral pharmacology to test whether stimulation of VTA-projecting neurons in the lateral hypothalamus, a central source of amylin, activates VTA amylin receptors to control energy balance. This will expand our knowledge by investigating the inputs to VTA amylin receptors, and will provide insight into sex and diet differences by testing male and female rats maintained on chow or high-fat diet (HFD). Specific Aim II evaluates the physiological relevance of VTA amylin receptors for long-term energy balance control in females by testing the feeding and body weight effects of VTA amylin receptor knockdown. This Aim also examines the phenotype of VTA amylin receptor-expressing cells in females with a combination of immunohistochemistry and in situ hybridization. The studies described in this application build upon the applicant's current K01 award by investigating the neural circuits and behavioral mechanisms by which VTA amylin receptor signaling controls energy balance, and by addressing dietary influences (e.g., palatable HFD or bland chow) on the VTA amylin system. These studies are also distinct from the aims of the K01 by exploring a novel and important topic: the role of sex differences in mesolimbic amylin signaling. These studies are designed to produce informative data that will serve as a generative starting point for follow-up questions to be addressed in an R01 application. The novel combination of in vivo and ex vivo techniques used in the proposed studies will further our understanding of the distributed actions of amylin in the brain for energy balance control, filling important gaps in our scientific knowledge that may further the development of novel amylin-based pharmacotherapies for the treatment of obesity.