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.

摘要 内脏脂肪组织(VAT)、肝脏和骨骼中过量脂肪的积累和异位脂肪的沉积 肌肉是艾滋病毒(PWH)患者心脏代谢性疾病高风险的重要因素 抗逆转录病毒疗法(ART)。虽然在抗逆转录病毒治疗的第一年，体重增加的可能性是众所周知的， 体重的多少是高度可变的，更重要的是，它是多余的身体脂肪和 导致心脏代谢合并症和并发症的异位脂质。我们假设在第一个阶段 以整合酶链转移抑制物(INSTI)为基础的治疗年正能量状态迅速开始 平衡、脂肪酸氧化受损和皮下脂肪组织(SAT)储存脂肪的能力受损 (部分由持续的T细胞介导的SAT炎症驱动)，这导致过量的脂质在 增值税、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个在艾滋病毒领域具有互补专业知识的既定专业人员领导 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 国家最先进的程序和技术，包括对驱动能源的因素进行全面评估 平衡，脂肪组织微吸脂，脂肪组织单细胞转录，SAT基因表达，以及 129例单纯PWH患者接受基于INSTI的ART治疗的第一年期间异位脂肪库的成像 以下具体目标：目标1：准确确定过剩脂肪在何时何地积累，包括 INSTI第一年的异位库存(胰岛素抵抗和糖尿病发展的标志)- 基于ART(当病毒抑制发生时)，以及在特定区域和仓库中是否储存多余的脂肪 是由过多的能量摄入、减少的能量消耗和/或减少的脂肪酸氧化所驱动的；目标2： 确定SAT体系结构、细胞组成和转录功能的具体变化 促进身体区域和仓库特有的异位脂肪积累；目标3：确定特定的变化 发生在SAT免疫环境和HIV储存库中，对脂肪细胞功能产生不利调节 和脂类储存。我们在INSTI为基础的ART的第一年中治疗幼稚PWH的纵向研究将 是第一个确定将能量平衡、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控的影响 脂肪转运途径参与了VAT和异位脂肪在肝脏和骨骼肌中的积累。 ART的第一年提供了一个预防肥胖增加和过度脂肪沉积的关键机会。 在腹内、肝脏和骨骼肌库中，从而降低心脏代谢疾病的风险 威尔斯亲王医院。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 开始抗逆转录病毒治疗后直接体脂和异位脂肪增加以预防和/或减轻 重症肝炎合并心脏代谢性疾病。