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

项目总结/摘要 胰岛素抵抗是2型糖尿病（T2 D）的关键驱动因素。有趣的是，艾滋病毒感染者（PLWH） 胰岛素抵抗和2型糖尿病，即使有病毒抑制。在确定是什么驱动胰岛素 尽管肥胖是人类的常见特征，但T2 D风险增加， 代谢不健康肥胖症（MUO）。新出现的观察结果指出，有两个因素促进了MUO的发生， 一般人群：1）线粒体含量减少， 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合成， 促进SCAT纤维化和胰岛素抵抗，而增加它显着阻断纤维化和改善 胰岛素敏感性考虑到这一点，我们和其他人观察到，PLWH显著增加了SCAT 纤维化，在SIV感染的猕猴中复制的反应。这促使我们怀疑PLWH是否也有 抑制米色脂肪细胞的生物合成，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， 表达特征标志物（Lin-：PDGFRa+：CD 81+）的成脂前体细胞（APC）的表达， 米色脂肪生物发生和SCAT纤维化之间的相互平衡。具体地，CD 81 + APC引起 SCAT中富含CD 81的米色脂肪细胞，而CD 81缺乏会导致SCAT纤维化， 小鼠的胰岛素抵抗。这些数据强调了SCAT中的CD 81 + APC可能 影响PLWH中MUO发展。我们还报道了米色/棕色脂肪是分支- 链氨基酸（BCAA），其循环水平与人胰岛素抵抗有关。激活 棕色/米色脂肪生物发生清除人体循环中的BCAA;事实上，BCAA清除是一种非侵入性的 棕色/米色脂肪活性指标。然而，在PLWH中尚未评估BCAA在脂肪中使用的影响。 我们假设，CD 81 + APC维持正常SCAT功能的能力降低，反映在SCAT 纤维化和受损的BCAA清除，驱动PLWH的胰岛素抵抗，逆转这一点可能会改善 代谢健康利用PLWH和未感染对照（包括MUO患者）的创新队列， 我们建议通过追求两个目标来测试这一假设，每个目标都将一项全面的人类研究与 创新小鼠模型的机制研究。在目标1中，我们研究了CD 81 + APC的丢失在多大程度上影响了细胞的增殖。 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中的SCAT纤维化。在目标2中，我们探测脂肪 BCAA的清除作为PLWH中葡萄糖稳态的决定因素，并确定破坏 米色/棕色脂肪BCAA使用对SAT纤维化和小鼠代谢健康的影响。通过验证机械指数， 预测MUO的SCAT健康（CD 81 + APC、纤维化、BCAA清除），并利用该指数改善 胰岛素敏感性，我们可能能够揭示新的方法来延长PLWH的代谢健康寿命。

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.