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

描述(由申请人提供)：建议的研究描述了一项关于新陈代谢的神经内分泌调节的指导性培训计划，旨在为应聘者提供必要的技能和资源，使他能够实现在研究型大学发展独立神经生物学家的长期目标。西奈山医学院的医学系拥有完善的课程和最先进的分析仪器。首席导师Christoph Buettner博士是一位知名的研究人员，在能量代谢领域备受尊敬，而联合导师则是代谢组学、肠脑沟通和减肥手术以及代谢综合征方面的权威人士。来自这些专家的丰富的机构资源和出色的指导将为候选人发展独立性提供理想的培训环境。该研究计划的重点是中枢胰岛素的作用及其在支链氨基酸(BCAA)代谢调节中的作用。将生理学和代谢靶向工具与遗传学、药理学和外科方法相结合，建议中描述的实验将确定：(1)下丘脑胰岛素对循环支链氨基酸及其中间体的作用；(3)受中枢胰岛素作用控制的肝脏支链氨基酸分解代谢；(3)Roux-en-Y胃旁路手术(RYGB)对全身和肝脏支链氨基酸代谢的影响，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支链氨基酸动态平衡的理解，这种动态平衡是由下丘脑胰岛素控制的，并解释了这种平衡如何在肥胖和糖尿病中受到干扰。重要的是，确认中枢胰岛素作用是RYGB成功改善支链氨基酸代谢的机制，有望在未来开发模拟手术诱导效应的非侵入性药物治疗。

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.