Assessing the Interrelationship Between Adipose Tissue Thermogenesis and Fibrosis in the Metabolic Health of People Living with HIV

评估艾滋病毒感染者代谢健康中脂肪组织产热与纤维化之间的相互关系

• 批准号: 10626188
• 负责人: PETER W HUNT
• 金额: $ 56.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-03 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626188
• 关键词: Acquired Immunodeficiency Syndrome; Adipocytes; Adipose tissue; Adrenergic Receptor; Aging; Attention; Automobile Driving; Biogenesis; Biological Markers; Blood Banks; Body mass index; Branched-Chain Amino Acids; Brown Fat; CD4 Lymphocyte Count; CD81 gene; Cells; Chronic; Cytomegalovirus; Data; Development; Diabetes Mellitus; Diet; Effectiveness; Elderly; Equilibrium; Fatty acid glycerol esters; Fibrosis; General Population; Genetic Predisposition to Disease; Goals; HIV; Health; Human; Impairment; Individual; Infection; Insulin Resistance; Isoleucine; Lead; Leucine; Life Style; Link; Macaca; Measures; Metabolic; Mind; Mitochondria; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Persons; Pharmaceutical Preparations; Population; Positron-Emission Tomography; Prevalence; Process; Production; Reporting; Resources; Risk Factors; Role; SIV; Testing; Thermogenesis; Tissues; Valine; Viral; Work; blood glucose regulation; co-infection; cohort; diabetes risk; glucose tolerance; healthspan; human study; improved; indexing; innovation; insulin sensitivity; metabolic phenotype; mouse model; obese person; precision medicine; precursor cell; preservation; response; subcutaneous; tool; trait

PROJECT SUMMARY/ABSTRACT Insulin resistance is a key driver of type 2 diabetes (T2D). Interestingly, people living with HIV (PLWH) are prone to developing insulin resistance and T2D, even with viral suppression. In determining what drives this insulin resistance, we have focused on the fact that whereas obesity is a common trait in humans, T2D risk is increased by “metabolically unhealthy obesity” (MUO). Emerging observations point to two factors promoting MUO in the general population: 1) reduced mitochondrial content and fewer mitochondria-enriched “beige” adipocytes in the subcutaneous fat (SCAT) and 2) Development of SCAT fibrosis. Moreover, reducing beige fat biogenesis in mice promotes SCAT fibrosis and insulin resistance, whereas increasing it remarkably blocks fibrosis and improves insulin sensitivity. With this in mind, we and others have observd that PLWH have markedly increased SCAT fibrosis, a response replicated in SIV-infected macaques. This prompts us to wonder whether PLWH also have suppressed beige adipocyte biogenesis, and what factors dictate this. To this end, we recently identified a subset of adipogenic precursor cells (APCs) expressing signature markers (Lin–: PDGFRa+: CD81+) that control a reciprocal balance between beige fat biogenesis and SCAT fibrosis. Specifically, CD81+ APCs give rise to mitochondria-rich beige adipocytes in the SCAT, whereas CD81 deficiency causes both SCAT fibrosis and insulin resistance in mice. These data highlight the intriguing possibility that CD81+ APCs in the SCAT may influence development of MUO in PLWH. We also reported that beige/brown fat is a metabolic sink for branched- chain amino acids (BCAAs), the circulating levels of which are linked to human insulin resistance. Activating brown/beige fat biogenesis clears circulating BCAAs in humans; indeed, BCAA clearance is a noninvasive indicator of brown/beige fat activity. However, the impact of BCAA usage in fat has not been assessed in PLWH. We hypothesize that a reduced capacity of CD81+ APCs to maintain normal SCAT function, reflected by SCAT fibrosis and impaired BCAA clearance, drives insulin resistance in PLWH, and that reversing this may improve metabolic health. Leveraging an innovative cohort of PLWH and uninfected controls, including those with MUO, we propose to test this hypothesis by pursuing two aims, each integrating a comprehensive human study with mechanistic studies in innovative mouse models. In Aim 1, we examine the extent to which loss of CD81+ APC abundance, proliferative capacity, or differentiation potential predicts SCAT fibrosis and insulin resistance in PLWH, and whether manipulating these cells can modulate SCAT fibrosis in mice. In Aim 2, we probe adipose clearance of BCAAs as a determinant of glucose homeostasis in PLWH, and determine the impact of disrupting beige/brown fat BCAA usage on SAT fibrosis and metabolic health in mice. By validating a mechanistic index of SCAT health (CD81+ APCs, fibrosis, BCAA clearance) that predicts MUO, and leveraging this index to improve insulin sensitivity, we may be able to reveals new ways to prolong the metabolic healthspan of PLWH.

项目摘要/摘要 胰岛素抵抗是2型糖尿病(T2D)的关键驱动因素。有趣的是，艾滋病毒携带者(PLWH)很容易 导致胰岛素抵抗和T2D，即使在病毒抑制下也是如此。在确定是什么驱动了这种胰岛素 阻力，我们关注的是这样一个事实，尽管肥胖是人类的共同特征，但T2D风险增加 被称为“代谢不健康肥胖”(MUO)。新出现的观察指出了两个促进MUO的因素 一般人群：1)线粒体含量减少，线粒体丰富的“米色”脂肪细胞减少 皮下脂肪(SCAT)和2)SCAT纤维化的发展。此外，减少小鼠的米色脂肪生物生成 促进SCAT纤维化和胰岛素抵抗，而增加SCAT显著阻止纤维化并改善 胰岛素敏感性。考虑到这一点，我们和其他人已经观察到，PLWH显著增加了SCAT 纤维化，一种在感染SIV的猕猴身上复制的反应。这促使我们怀疑PLWH是否也有 抑制米色脂肪细胞的生物生成，以及是什么因素决定了这一点。为此，我们最近确定了一个子集 成脂前体细胞(APC)表达控制血管生成的标志物(LIN-：PDGFRA+：CD81+) 米色脂肪生物生成和SCAT纤维化之间的相互平衡。具体地说，CD81+APC引起 SCAT中富含线粒体的米色脂肪细胞，而CD81缺乏导致SCAT纤维化和 小鼠的胰岛素抵抗。这些数据突出了一个耐人寻味的可能性，即SCAT中的CD81+APC可能 影响PLWH中MUO的发展。我们还报道，米色/棕色脂肪是分枝脂肪的代谢库- 链氨基酸(BCAA)，其循环水平与人类胰岛素抵抗有关。正在激活 棕色/米色脂肪生物生成清除人类循环中的支链氨基酸；事实上，支链氨基酸清除是一种非侵入性的 棕色/米色脂肪活动的指示器。然而，PLWH尚未评估在FAT中使用支链氨基酸的影响。 我们假设CD81+APC维持正常SCAT功能的能力降低，这反映在SCAT上 纤维化和支链氨基酸清除受损推动了PLWH的胰岛素抵抗，逆转这种情况可能会改善 新陈代谢健康。利用PLWH和未感染控制措施的创新队列，包括那些患有MUO的人， 我们建议通过追求两个目标来检验这一假设，每个目标都将一项全面的人类研究与 创新小鼠模型的机理研究。在目标1中，我们检查了CD81+APC丢失的程度 丰度、增殖能力或分化潜能预测SCAT纤维化和胰岛素抵抗 PLWH，以及操纵这些细胞是否可以调节小鼠的SCAT纤维化。在目标2中，我们探索脂肪 清除支链氨基酸作为PLWH中葡萄糖稳态的决定因素，并确定干扰的影响 米色/棕色脂肪支链氨基酸在小鼠SAT纤维化和代谢健康中的应用。通过验证一个机械索引 预测MUO的SCAT健康状况(CD81+APC、纤维化、支气管炎清除)，并利用这一指数来改善 胰岛素敏感性，我们可能能够揭示延长PLWH代谢健康跨度的新方法。