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

项目摘要/摘要 肥胖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是 严重受限。胰淀素系统被认为是开发新型抗病毒药物的一个有前途的候选者。 肥胖症的药物治疗，如胰淀素激动剂，减少人类的食物摄入量和产生减肥作用 动物模型。腹侧被盖区(VTA)是一种中脑边缘核，在摄食和呼吸中起关键作用 有动机的行为，是一种与生理和药物相关的能量平衡的作用场所 胰淀素的作用。然而，VTA胰淀素受体介导的吞噬功能低下的机制仍然存在。 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是未知的。这项提议的首要目标是 确定VTA胰淀素受体信号转导的新神经解剖学和行为学机制 促进食欲不振和减肥，特别是关注性和饮食在这些影响中的作用。 这一奖项将促进申请者通过以下方式成为完全独立的私人投资公司 探索中边缘胰淀素信号转导的新主题，并为 未来的R01应用。《特定目标I》采用了病毒遗传学和行为学的创新结合 药理学测试刺激中枢神经下丘脑外侧VTA投射神经元 胰淀素的来源，激活VTA胰淀素受体以控制能量平衡。这将扩大我们的知识，通过 研究VTA胰淀素受体的输入，并通过测试提供对性别和饮食差异的洞察 雄性和雌性大鼠以食物或高脂饮食(HFD)维持。特定目标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胰淀素受体基因敲除对体重的影响。这一目的还检测了VTA淀粉酶的表型。 用免疫组织化学和原位杂交相结合的方法研究女性的受体表达细胞。这个 本申请中描述的研究建立在申请人目前的K01奖的基础上，通过调查神经 VTA胰淀素受体信号控制能量平衡的电路和行为机制 解决饮食对VTA胰淀素系统的影响(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，也与K01的目标截然不同 在中脑边缘的胰淀素信号中。这些研究旨在产生信息丰富的数据，这些数据将作为 R01应用程序中要解决的后续问题的生成性起点。新奇的组合 在拟议的研究中使用的体内和体外技术将进一步加深我们对分布式 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中的重要空白 可能会进一步开发以胰淀素为基础的治疗肥胖症的新药物疗法。

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.