Adipose-Specific Phosphatidic Acid Phosphatase Activity of Lipin 1 Regulates Systemic Insulin Sensitivity

摘要 在K01指导科学家发展奖的申请中，Andrew J.Lutkewitte博士概述了详细的 战略，以进一步加强他的研究培训，使用复杂的代谢和脂肪分析。他会的 利用这些方法发现脂肪不足驱动的全身性胰岛素抵抗的新介质 肥胖症患者的组织造脂能力。Lutkewitte博士目前是华盛顿大学博士后研究员 大学医学院老年医学和营养科学部。他在…方面有很强的背景 他将利用全身生理学和新陈代谢来研究代谢过程中的脂肪功能 压力。Lutkewitte博士的主要目标是成为脂代谢和 肥胖导致的胰岛素抵抗。他精心制定了一项具有完整职业生涯的研究战略 发展和指导计划，以确保实现这一目标。每一位被选中的导师都是 与这项提议直接相关的各自领域的专家。主要导师布莱恩·芬克博士 将协助动物和细胞培养模型的新陈代谢表征和分析。从Nada博士那里 Abumrad，他将学习间质血管分离，了解脂肪细胞的机制 分化和脂肪生成，以及脂肪摄取/输出的基础。加里·帕蒂博士将对勒克维特博士进行培训 靶向和非靶向代谢组学以及体内使用同位素示踪剂的代谢流量分析。 除了研究培训，Finck博士和一个“近邻”指导团队将为Lutkewitte博士提供 创建和维护一个成功的独立实验室的基本技能。脂肪组织的能力 调节脂肪储存(主要是甘油三酯)对于保持新陈代谢健康至关重要。事实上，两国之间的失衡 脂肪组织中脂肪的适当释放(脂肪分解)或合成(脂肪生成)增加了患 非酒精性脂肪性肝病、全身性胰岛素抵抗以及最终的2型糖尿病等病理改变。 然而，脂肪组织如何调节全身胰岛素敏感性的基本机制仍不清楚。 最近的证据表明，磷脂1的底物磷脂酸是一种磷脂酸酸性磷酸酶 在血液中含量很高，对胰岛素敏感的组织，如骨骼肌有有害影响 还有肝脏。这项工作的目标是：[1]确定翻译后修饰、乙酰化、 脂蛋白1的活性和细胞定位，[2]发现调节脂蛋白1的特定乙酰化赖氨酸残基，[3] 定义脂肪组织脂1如何调节全身新陈代谢和胰岛素敏感性，并[4]确定如何 磷脂酸和类似的脂类介导了这些作用。这一研究进展的最终目标是发展 勒克维特博士成为了一名富有成效的独立调查员。把研究和职业培训结合起来 这里概述的发展计划将为他提供知识和专业知识，以确保独立的 学术地位和R01型资金。

ABSTRACT In this K01 Mentored Scientist Development Award application, Dr. Andrew J. Lutkewitte outlines a detailed strategy to further enhance his research training using sophisticated metabolic and lipidomic analysis. He will utilize these approaches to discover novel mediators of systemic insulin resistance driven by insufficient adipose tissue lipogenic capacity in obesity. Dr. Lutkewitte is currently a postdoctoral research fellow at Washington University School of Medicine’s Division of Geriatrics and Nutritional Sciences. He has a strong background in whole-body physiology and metabolism that he will draw upon to investigate adipose function during metabolic stress. A primary goal of Dr. Lutkewitte is to become and independent investigator in lipid metabolism and obesity-induced insulin resistance. He has carefully developed a research strategy with an integrated career development and mentoring plan to ensue realization of this goal. Each of the chosen mentors are leading experts in their respective fields which are directly related to this proposal. The primary mentor Dr. Brian Finck will assist with the metabolic characterization and analysis of both animal and cell culture models. From Dr. Nada Abumrad, he will learn stromal vascular fraction isolations, gain understanding about mechanisms of adipocyte differentiation and lipogenesis, and fundamentals of lipid uptake/export. Dr. Gary Patti will train Dr. Lutkewitte in both targeted and untargeted metabolomics as well as metabolic flux analysis using isotopic tracers in vivo. Besides research training, Dr. Finck and a “Near Peer” mentoring team will provide Dr. Lutkewitte with the essential skills to initiate and maintain a successful, independent laboratory. The ability of adipose tissue to regulate lipid stores (mainly, triglycerides) is vital for preserving metabolic health. In fact, an imbalance between the appropriate release (lipolysis) or synthesis (lipogenesis) of lipids in adipose tissue increases the risk of pathologies such as non-alcoholic fatty liver disease, systemic insulin resistance and ultimately type 2 diabetes. Yet, the fundamental mechanisms of how adipose tissue regulates systemic insulin sensitivity remain unclear. Recent evidence suggests that phosphatidic acid, the substrate for lipin 1, a phosphatidic acid phosphatase, is present at high levels in the blood and has deleterious effects in insulin sensitive tissues such as skeletal muscle and liver. The goals of this work are to: [1] determine how the posttranslational modification, acetylation, effects lipin 1 activity and cellular localization, [2] discover the specific acetylated lysine residues regulating lipin 1, [3] define how adipose tissue lipin 1 regulates whole-body metabolism and insulin sensitivity, and [4] to identify how phosphatidic acid and similar lipids mediate these effects. The end goal of this research progression is to develop Dr. Lutkewitte into a productive, independent investigator. Together the training in research and career development plan outlined here will provide him with the knowledge and expertise to secure an independent academic position and R01-type funding.