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: 10570223
• 负责人: SHEILA COLLINS
• 金额: $ 83.66万
• 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/10570223
• 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; Human; Image; Immune; Immunology; Impairment; Indirect Calorimetry; Inflammation; Inflammatory; Insulin Resistance; Integrase; Intervention Studies; Intra-abdominal; 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; Risk; Risk Reduction; 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; 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.

摘要 内脏脂肪组织（VAT）、肝脏和骨骼中的过量脂肪积聚和异位脂质沉积 肌肉对HIV感染者（PWH）心脏代谢疾病的高风险有很大贡献， 抗逆转录病毒疗法（ART）。虽然ART治疗第一年体重增加的可能性是公认的， 体重的量是高度可变的，更重要的是，它是多余的身体脂肪的积累， 异位脂质导致心脏代谢合并症和并发症。我们假设在第一次 一年的整合酶链转移抑制剂（CITRI）为基础的治疗有一个积极的能量状态迅速发病 平衡、脂肪酸氧化受损和皮下脂肪组织（SAT）储存脂质的能力受损 （部分由持续的T细胞介导的SAT炎症驱动），这导致多余的脂质沉积在 VAT、肝脏和骨骼肌进一步抑制这些器官和组织正常运作的能力。 这项多学科研究将由三名在艾滋病毒领域具有互补专长的资深PI领导 临床研究、脂肪细胞生物学和生理学、营养学、人体代谢和成像。我们将利用 最先进的程序和技术，包括对能源驱动因素的全面评估 平衡，脂肪组织显微吸脂术，脂肪组织单细胞转录组学，SAT基因表达， 在129例未经治疗的PWH中，在基于INSTI的ART的第一年期间，异位脂质沉积成像，以满足 具体目标如下：目标1：精确确定多余脂肪积聚的时间和地点，包括 异位贮库（胰岛素抵抗和糖尿病发展的标志），在第一年的胰岛素抵抗， 基于ART（当病毒抑制发生时），以及是否在特定区域和仓库中储存过量脂肪 由过量的能量摄入、减少的能量消耗和/或减少的脂肪酸氧化驱动;目标2： 确定SAT结构、细胞组成和转录组学特征的具体变化， 有助于身体部位和贮库特异性异位脂肪堆积;目的3：确定特异性变化 发生在SAT免疫环境和HIV储库中，其不利地调节脂肪细胞功能 和脂质储存。我们在INSTI为基础的ART治疗的第一年对未经治疗的PWH进行的纵向研究将 成为第一个确定能量平衡，脂肪酸氧化，SAT架构和 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VAT和异位脂质在肝脏和骨骼肌中的积累。 抗逆转录病毒疗法的第一年提供了一个关键的机会，以防止增加肥胖和过度脂肪沉积 在腹腔内，肝脏和骨骼肌仓库，从而降低心脏代谢疾病的风险， PWH。这些数据将为未来的临床和药物干预研究确定目标，以预防或重新 在ART启动后直接体脂和异位脂质增加，以预防和/或减少 心脏代谢疾病