Adipocyte lipolysis of oxidized neutral lipids regulates insulin signaling during acute stress.

氧化中性脂质的脂肪细胞脂肪分解在急性应激期间调节胰岛素信号传导。

• 批准号: 9911180
• 负责人: Katelyn Wellcome Ahern
• 金额: $ 1.93万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911180
• 关键词: Acute; Adipocytes; Adipose tissue; Affect; Agonist; Alternative Therapies; Animal Model; Antioxidants; Attenuated; Automobile Driving; Biological Assay; Blood Glucose; Catecholamines; Chemicals; Chronic; Complex; Critical Illness; Dangerousness; Development; Diabetes Mellitus; Dissociation; FRAP1 gene; Fatty Acids; Functional disorder; Hyperglycemia; Hypoglycemia; Hypovolemics; Impairment; In Vitro; Injury; Insulin; Insulin Resistance; Knockout Mice; Link; Lipase; Lipids; Lipolysis; Mediating; Methods; Modeling; Monitor; Mus; Operative Surgical Procedures; Oxidative Stress; Oxides; Patients; Phosphotransferases; Postoperative Complications; Postoperative Period; Production; Protein Kinase; Reactive Oxygen Species; Research; Research Personnel; Research Project Grants; Risk; Role; Stress; Sympathetic Nervous System; Testing; Tissues; Training; Trauma; Triglycerides; Work; acute stress; attenuation; beta-adrenergic receptor; biological adaptation to stress; blood glucose regulation; glucose uptake; improved; insulin regulation; insulin signaling; liquid chromatography mass spectrometry; mTOR inhibition; meetings; mortality; new therapeutic target; novel; oxidation; oxidized lipid; receptor; symposium; targeted treatment

PROJECT SUMMARY/ABSTRACT Acute hyperglycemia and systemic insulin resistance (IR) often develop after injury or surgery. This stress response, appropriately known as critical illness diabetes, leads to increased post-operative complications and mortality. Insulin administration reduces hyperglycemia in some patients, but has a risk of hypoglycemia. The underlying mechanism of post-operative IR is largely unknown, which limits alternative therapies and emphasizes the need to elucidate the pathophysiology. It is, however, known that surgical animal models rapidly develop adipose IR. Impaired insulin action in adipose alone can result in whole body IR and hyperglycemia. Therefore, this proposal will focus on how adipocyte lipolysis contributes to stress-induced IR. Inhibition of mTOR complexes 1 and 2, kinase complexes integral to insulin signaling, is associated with the onset of IR. Our previous work demonstrates that catecholamine-induced attenuation of insulin signaling requires lipolysis of the neutral lipids triacylglycerols (TAGs) and causes mTOR complex dissociation. We recently observed that the presence of lipolytic products of oxidized neutral lipids (oxNL) induces mTOR complex dissociation. We hypothesize that lipolysis breaks down oxidized TAGs into oxidized fatty acids (oxFAs), which cause mTOR complex dissociation and attenuation of insulin signaling within adipocytes during stress response. To this purpose, we propose the following aims. In Aim 1, we will define the oxFAs responsible by examining in vitro whether oxidation of known polyunsaturated FAs generates products that cause mTOR complex dissociation. Additionally, we will elucidate the type responsible by class-specific chemical derivitization of oxFAs. In Aim 2, we will determine the role of adipose lipolysis and oxFA-mediated mTOR complex inhibition during the acute stress response by treating wild-type and adipose-specific adipose triglyceride lipase null mice with β receptor agonists. We will also stimulate the onset of the stress response by subjecting mice to a hypovolemic model of acute trauma. The potential effect of oxFA production on mTOR complex dissociation and the development of IR within adipose will be determined. Our work will elucidate a novel role for oxNLs and their lipolytic products in the regulation of insulin signaling. Defining the mechanism by which catecholamine- stimulated lipolysis attenuates insulin signaling will provide novel therapeutic targets for improved post-operative glucose homeostasis. The research project proposed will be carried out in conjunction with a rigorous training plan composed of the following: integrative coursework and interactive training, participation in research meetings and seminars, participation in scientific conferences, and professional development. The combination of the proposed research along with an active training plan will yield meaningful contributions to the field and the training required to excel as a successful independent researcher.

项目概要/摘要 急性高血糖和全身胰岛素抵抗（IR）通常在受伤或手术后发生。这种压力 反应，适当地称为危重病糖尿病，会导致术后并发症增加和 死亡。胰岛素治疗可降低某些患者的高血糖，但存在低血糖的风险。这 术后 IR 的潜在机制在很大程度上尚不清楚，这限制了替代疗法和 强调需要阐明病理生理学。然而，众所周知，手术动物模型迅速 发展脂肪 IR。仅脂肪中的胰岛素作用受损就会导致全身胰岛素抵抗和高血糖。 因此，本提案将重点关注脂肪细胞脂肪分解如何促进应激诱导的 IR。 mTOR 复合物 1 和 2（胰岛素信号转导不可或缺的激酶复合物）的抑制与 IR 的发作。我们之前的工作表明，儿茶酚胺诱导的胰岛素信号减弱 需要中性脂质三酰甘油 (TAG) 的脂解并导致 mTOR 复合物解离。我们 最近观察到氧化中性脂质 (oxNL) 的脂解产物的存在会诱导 mTOR 复合物 解离。我们假设脂肪分解将氧化的 TAG 分解为氧化的脂肪酸 (oxFA)， 导致脂肪细胞内 mTOR 复合物解离和胰岛素信号减弱 应激反应。 为此，我们提出以下目标。在目标 1 中，我们将定义负责的 oxFA 体外检查已知多不饱和 FA 的氧化是否会产生导致 mTOR 的产物 复杂的解离。此外，我们将通过特定类别的化学衍生化来阐明负责的类型 oxFA。在目标 2 中，我们将确定脂肪分解和 oxFA 介导的 mTOR 复合物抑制的作用 通过治疗野生型和脂肪特异性脂肪甘油三酯脂肪酶无效小鼠的急性应激反应 与β受体激动剂合用。我们还将通过对小鼠进行刺激来刺激应激反应的发生 急性创伤低血容量模型。 oxFA 产生对 mTOR 复合物解离和的潜在影响 脂肪内 IR 的发展将被确定。我们的工作将阐明 oxNL 的新作用及其 脂解产物在胰岛素信号传导中的调节作用。定义儿茶酚胺的机制 刺激脂肪分解减弱胰岛素信号传导将为改善术后效果提供新的治疗靶点 葡萄糖稳态。 拟议的研究项目将与严格的培训计划一起进行 以下内容：综合课程和互动培训、参加研究会议和研讨会， 参加科学会议和专业发展。拟议研究的结合 加上积极的培训计划将为该领域做出有意义的贡献，并提供卓越所需的培训 作为一名成功的独立研究员。