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

描述（由申请人提供）：拟议的研究描述了代谢的神经内分泌调节的指导培训计划，旨在为候选人提供必要的技能和资源，使其能够实现在研究型大学发展独立神经生物学家职业生涯的长期目标。西奈山医学院的医学系拥有完善的项目，并配备了最先进的分析仪器。主要导师Christoph Buettner博士是一位成熟的研究者，在能量代谢领域备受尊敬，而共同导师则是代谢组学，肠脑沟通和减肥手术以及代谢综合征的权威。这些专家丰富的机构资源和出色的指导将为候选人提供理想的培训环境，以培养独立性。该研究计划的重点是中枢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、药理学和外科手术方法相结合，该提案中描述的实验将确定：（1）下丘脑胰岛素对循环BCAA及其中间体的作用;（2）由中枢胰岛素作用控制的肝脏BCAA催化剂;（3）Roux-en-Y胃旁路术（RYGB）对全身和肝脏BCAA代谢的影响，以及RYGB术后中枢胰岛素作用的潜在作用。拟议的研究将促进我们对下丘脑胰岛素控制下的BCAA体内平衡的理解，并解释这在肥胖和糖尿病中是如何被扰乱的。重要的是，将中枢胰岛素作用确定为RYGB成功改善BCAA代谢的机制，为未来开发模拟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.