Role of brain insulin in the regulation of branched-chain amino acid metabolism

描述（由申请人提供）：拟进行的研究描述了一项关于神经内分泌调节代谢的指导培训计划，旨在为候选人提供必要的技能和资源，使他能够实现在研究型大学发展成为独立神经生物学家的长期目标。西奈山医学院医学系拥有完善的项目，配备了最先进的分析仪器。主要导师Christoph Buettner博士是一位知名的研究者，在能量代谢领域备受尊敬，而共同导师则是代谢组学、肠脑通讯、减肥手术和代谢综合征方面的权威。丰富的机构资源和优秀的专家指导将为候选人提供一个理想的培养环境，培养他们的独立性。该研究计划侧重于中心胰岛素作用及其在支链氨基酸（BCAA）代谢调节中的作用。将生理和代谢靶向工具与遗传、药理学和外科方法相结合，提案中描述的实验将确定：(1)下丘脑胰岛素对循环BCAAs及其中间体的作用；(1)受胰岛素中枢作用控制的肝脏BCAA分解代谢；(3) Roux-en-Y胃旁路手术（RYGB）对全身和肝脏BCAA代谢的影响，以及RYGB手术后中枢胰岛素作用的潜在作用。提出的研究将促进我们对下丘脑胰岛素控制下的BCAA稳态的理解，并解释肥胖和糖尿病是如何扰乱BCAA稳态的。重要的是，确定中枢胰岛素作用作为RYGB成功改善BCAA代谢的机制，为未来开发模仿手术诱导效应的非侵入性药物治疗提供了希望。

DESCRIPTION (provided by applicant): The proposed research describes a mentored training program in neuroendocrine regulation of metabolism, designed to provide the candidate the necessary skills and resources that will allow him to achieve the long- term goal of developing a career as an independent neurobiologist at a research-oriented university. Department of Medicine at Mount Sinai School of Medicine has well-established programs with state-of-the-art analytical instrumentations. The primary mentor, Dr. Christoph Buettner, is an established investigator and is well respected in the field of energy metabolism, while the co-mentors are authorities in metabolomics, gut- brain communication and bariatric surgery, and metabolic syndrome. The abundant institutional resources and excellent mentorship from these experts will provide an ideal training environment for the candidate to develop independence. The research plan focuses on central insulin action and its role in the regulation of branched- chain amino acid (BCAA) metabolism. Combining physiological and metabolic targeting tools with genetic, pharmacological, and surgical approaches, the experiments described in the proposal will identify: (1) the role of hypothalamic insulin on circulating BCAAs and their intermediates; () hepatic BCAA catabolism as controlled by the central insulin action; and (3) systemic and liver BCAA metabolism affected by Roux-en-Y gastric bypass (RYGB) surgery, and the potential role of central insulin action after RYGB. The proposed studies will advance our understanding of BCAA homeostasis that is under the control of hypothalamic insulin, and explain how this is perturbed in obesity and diabetes. Importantly, identifying central insulin action as a mechanism through which RYGB successfully improves BCAA metabolism holds promise for future development of non-invasive pharmacological treatments that mimic the surgery-induced effects.