Pathophysiology of Metabolically Detrimental Changes in Adipose Distribution, Adipocyte Function, and Adipose Immune Environment on Antiretroviral Therapy

抗逆转录病毒治疗中脂肪分布、脂肪细胞功能和脂肪免疫环境代谢有害变化的病理生理学

• 批准号: 10364376
• 负责人: SHEILA COLLINS
• 金额: $ 85.47万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364376
• 关键词: Academic Medical Centers; Adipocytes; Adipose tissue; Age; Architecture; Automobile Driving; Body Regions; Body Weight; Body fat; CD4 Positive T Lymphocytes; Cardiometabolic Disease; Cell physiology; Cells; Cholesterol; Clinical; Clinical Research; Data; Defect; Deposition; Development; Diabetes Mellitus; Energy Intake; Energy Metabolism; Environment; Fatty acid glycerol esters; Flow Cytometry; Functional disorder; Future; Gene Expression; General Population; Genes; Goals; HIV; HIV Infections; HIV Seronegativity; HIV antiretroviral; Human; Image; Immune; Immunology; Impairment; Indirect Calorimetry; Inflammation; Inflammatory; Insulin Resistance; Integrase; Intervention Studies; Intra-abdominal; Lead; Link; Lipids; Liver; Longitudinal Studies; Measurement; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Modernization; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathway interactions; Persons; Pharmacologic Substance; Physiology; Procedures; Regimen; Resistance development; Risk; Role; Science; Skeletal Muscle; Suction Lipectomy; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Tissues; Transferase; Triglycerides; Viral; Visceral; Weight; Weight Gain; X-Ray Computed Tomography; adipocyte biology; antiretroviral therapy; base; cardiometabolic risk; cardiometabolism; comorbidity; cytotoxic; density; doubly-labeled water; energy balance; fatty acid oxidation; high risk; immune activation; inhibitor; lipid transport; multidisciplinary; nutrition; prevent; radiological imaging; subcutaneous; transcriptomics

Abstract Excess fat accumulation and deposition of ectopic lipid in visceral adipose tissue (VAT), the liver and skeletal muscles contribute substantially to the high risk for cardiometabolic disease in persons with HIV (PWH) on antiretroviral therapy (ART). While the potential for weight gain during the first year of ART is well-recognized, the amount of weight is highly variable, and more importantly, it is the accumulation of excess body fat and ectopic lipid that drives cardiometabolic comorbidities and complications. We hypothesize that during the first year of integrase strand transfer inhibitor (INSTI)-based therapy there is rapid onset of a state of positive energy balance, impaired fatty acid oxidation, and impaired ability of subcutaneous adipose tissue (SAT) to store lipids (driven in part by persistent T cell-mediated SAT inflammation), which leads to the deposition of excess lipids in VAT, the liver and skeletal muscle further inhibiting the ability of these organs and tissues to function normally. This multi-disciplinary study will be led by three established PIs with complementary expertise in the fields of HIV clinical research, adipocyte biology and physiology, nutrition, human metabolism, and imaging. We will leverage state-of-the-science procedures and technologies including comprehensive assessment of factors driving energy balance, adipose tissue micro-liposuction, adipose tissue single cell transcriptomics, SAT gene expression, and imaging of ectopic lipid depots during the first year of INSTI-based ART in 129 treatment-naïve PWH to meet the following specific aims: Aim 1: To determine precisely when and where excess fat accumulates, including ectopic depots (hallmarks for insulin resistance and development of diabetes) during the first year of INSTI- based ART (when viral suppression occurs), and whether the storage of excess fat in specific regions and depots is driven by excess energy intake, reduced energy expenditure, and/or reduced fatty acid oxidation; Aim 2: To determine the specific changes in the SAT architecture, cellular composition, and transcriptomic features that contribute to body region and depot-specific ectopic fat accumulation; Aim 3: To determine the specific changes that occur in the SAT immune environment and HIV reservoir that adversely modulate adipocyte cellular function and lipid storage. Our longitudinal study in treatment-naïve PWH during the first year of INSTI-based ART will be the first to identify mechanisms linking changes in energy balance, fatty acid oxidation, SAT architecture and function, and the impact of the SAT immune environment on adipocyte plasticity and adipocyte regulatory and lipid trafficking pathways involved in the accumulation of VAT and ectopic lipid in the liver and skeletal muscle. The first year of ART provides a critical opportunity to prevent increased adiposity and excessive fat deposition in the intra-abdominal, liver and skeletal muscle depots, and thus reduce the risk for cardiometabolic disease in PWH. These data will identify targets for future clinical and pharmaceutical intervention studies to prevent or re- direct body fat and ectopic lipid gain after ART initiation to prevent and/or reduce the growing burden of cardiometabolic diseases in PWH.

抽象的 脂肪脂质过多的脂肪积累和在内脏脂肪组织（VAT），肝脏和骨骼中的沉积 肌肉在HIV患者（PWH）上对心脏代谢疾病的高风险做出了重大贡献 抗逆转录病毒疗法（ART）。虽然在艺术的第一年中，体重增加的潜力得到了很好的认可，但 体重的量高度可变，更重要的是，多余的体内脂肪的积累和 驱动心脏代谢合并症和并发症的生态脂质。我们假设在第一个 基于整合酶链转移抑制剂（Insti）的疗法的年份正面能量状态迅速发作 平衡，脂肪酸氧化受损以及皮下脂肪组织（SAT）储存脂质的能力受损 （部分由持续的T细胞介导的SAT注射驱动），这导致过量脂质的沉积 增值税，肝脏和骨骼肌进一步抑制了这些器官和组织正常起作用的能力。 这项多学科研究将由三个既定的PI领导，在艾滋病毒领域具有完整的专业知识 临床研究，脂肪细胞生物学和生理学，营养，人类代谢和成像。我们将利用 最先进的程序和技术，包括全面评估驱动能量的因素 平衡，脂肪组织微作物，脂肪组织单细胞转录组学，SAT基因表达和 在129次未经治疗的PWH中，基于Insti Art的第一年的Ecopic脂质沉积物成像 以下具体目的：目标1：确切确定何时何地累积脂肪，包括 学院第一年期间的异位沉积物（胰岛素抵抗和糖尿病耐药性的标志） 基于ART（发生病毒抑制时），以及在特定区域和沉积物中多余的脂肪存储是否存在 由过量的能量摄入，减少能量消耗和/或减少脂肪酸氧化驱动；目标2：到 确定SAT体系结构，蜂窝组成和转录组特征的特定变化 有助于身体区域和沉积物特异性的生态脂肪积累；目标3：确定具体更改 发生在SAT免疫环境和HIV储层中，可不利地调节脂肪细胞功能 和脂质存储。我们在基于Insti Art的第一年的治疗中的纵向研究将 成为第一个确定能量平衡变化，脂肪酸氧化，SAT结构和 功能，以及SAT免疫环境对脂肪细胞可塑性和脂肪细胞调节的影响 脂质运输途径参与肝脏和骨骼肌中增值税和生态脂质的积累。 艺术的第一年为防止肥胖和多余的脂肪沉积提供了关键的机会 在腹内，肝脏和骨骼肌沉积中，从而降低了心脏代谢疾病的风险 PWH。这些数据将确定未来临床和药物干预研究的目标，以预防或重新 直接体内脂肪和生态脂质在艺术倡议后，以预防和/或减少日益增长的燃烧 PWH中的心脏代谢疾病。