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）的关键驱动力。有趣的是，患有艾滋病毒（PLWH）的人容易发生 即使受到病毒抑制，也会产生胰岛素抵抗和T2D。在确定驱动这种胰岛素的是什么 抵抗性，我们集中于这样一个事实，尽管肥胖是人类的常见特征，但T2D风险增加了 通过“代谢不健康的肥胖”（MUO）。新兴观察指出了促进MUO的两个因素 一般人群：1）降低线粒体含量，较少的线粒体含有富含米色的脂肪细胞 皮下脂肪（SCAT）和2）发育SCAT纤维化。此外，减少小鼠米色脂肪生物发生 促进SCAT纤维化和胰岛素耐药性，而增加它会明显阻断纤维化并改善 胰岛素灵敏度。考虑到这一点，我们和其他人观察到PLWH明显增加了SCAT 纤维化，在SIV感染的猕猴中复制的反应。这促使我们想知道PLWH是否也 抑制米色脂肪细胞生物发生，以及什么因素决定了这一点。为此，我们最近确定了一个子集 表达签名标记（Lin–：PDGFRA+：CD81+）的脂肪生成前体细胞（APC）的控制 米色脂肪生物发生和粪便纤维化之间的相互平衡。具体而言，CD81+ APC产生 SCAT中富含线粒体的米色脂肪细胞，而CD81缺乏会导致SCAT纤维化和 小鼠胰岛素抵抗。这些数据突出了SCAT中CD81+ APC的有趣可能性 影响PLWH中MUO的发展。我们还报道说，米色/棕色脂肪是分支的代谢水槽 链氨基酸（BCAA），其循环水平与人类胰岛素抵抗有关。激活 棕/米色脂肪生物发生清除了人类循环的BCAA。确实，BCAA清除是无创的 棕色/米色脂肪活性的指标。但是，BCAA在脂肪中使用的影响尚未在PLWH中评估。 我们假设CD81+ APC的容量降低了维持正常SCAT功能的能力，SCAT反映了 纤维化和BCAA间隙受损，在PLWH中驱动胰岛素抵抗，并且逆转可能会改善 代谢健康。利用创新的PLWH和未感染的控件，包括具有MUO的对照， 我们建议通过追求两个目标来检验这一假设 创新小鼠模型中的机械研究。在AIM 1中，我们检查了CD81+ APC的丢失程度 抽象，增殖能力或分化潜在预测SCAT纤维化和胰岛素抵抗 PLWH以及是否操纵这些细胞可以调节小鼠的SCAT纤维化。在AIM 2中，我们探测脂肪 在PLWH中清除BCAA作为葡萄糖稳态的决定者，并确定破坏的影响 小鼠SAT纤维化和代谢健康的米色/棕色脂肪BCAA使用。通过验证一个机械索引 SCAT Health（CD81+ APC，纤维化，BCAA清除率）预测MUO，并利用此指数改进 胰岛素敏感性，我们可能能够揭示延长PLWH代谢健康的新方法。