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

摘要 在K 01指导科学家发展奖申请中，Andrew J. Lutkewitte博士概述了一个详细的 战略，以进一步加强他的研究训练，使用先进的代谢和脂质组学分析。他将 利用这些方法来发现由脂肪不足驱动的系统性胰岛素抵抗的新介质， 肥胖症的组织脂肪生成能力Lutkewitte博士目前是华盛顿的博士后研究员 大学医学院老年医学和营养科学部。他有很强的背景， 全身生理学和代谢，他将利用研究代谢过程中的脂肪功能 应力Lutkewitte博士的主要目标是成为脂质代谢的独立研究者， 肥胖引起的胰岛素抵抗他精心制定了具有综合职业生涯的研究策略 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 与本提案直接相关的各自领域的专家。布莱恩·芬克博士Brian Finck 将有助于动物和细胞培养模型的代谢表征和分析。娜达医生 Abumrad，他将学习基质血管成分分离，了解脂肪细胞的机制， 分化和脂肪生成，以及脂质摄取/输出的基本原理。加里帕蒂医生会训练卢奇威特医生 靶向和非靶向代谢组学以及使用同位素示踪剂的体内代谢通量分析。 除了研究培训，芬克博士和一个“近同行”指导小组将为Lutkewitte博士提供 基本技能，以启动和维持一个成功的，独立的实验室。脂肪组织的能力 调节脂质储存（主要是甘油三酯）对保持代谢健康至关重要。事实上， 脂肪组织中脂质的适当释放（脂解）或合成（脂肪生成）增加了以下风险： 病理学如非酒精性脂肪肝、全身性胰岛素抵抗和最终的2型糖尿病。 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，磷脂酸，脂蛋白1，磷脂酸磷酸酶的底物， 在血液中以高水平存在，并对胰岛素敏感组织如骨骼肌 和肝脏。这项工作的目标是：[1]确定翻译后修饰，乙酰化，如何影响 脂蛋白1活性和细胞定位，[2]发现了调节脂蛋白1的特定乙酰化赖氨酸残基，[3] 定义脂肪组织lipin 1如何调节全身代谢和胰岛素敏感性，并[4]确定如何 磷脂酸和类似的脂质介导这些作用。这一研究进展的最终目标是开发 博士变成一个高效的独立调查员。研究和职业培训相结合 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R 01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.