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.

项目概要/摘要 胰岛素抵抗是 2 型糖尿病 (T2D) 的关键驱动因素。 甚至在病毒抑制的情况下发展胰岛素抵抗和 T2D 以确定驱动胰岛素的因素。 抵抗力，我们重点关注这样一个事实：虽然肥胖是人类的常见特征，但 T2D 风险会增加 新出现的观察结果表明，有两个因素会促进 MUO 的发生。 一般人群：1）线粒体含量减少，线粒体中富含线粒体的“米色”脂肪细胞减少 皮下脂肪 (SCAT) 和 2) SCAT 纤维化的发展 此外，减少小鼠米色脂肪的生物合成。 促进 SCAT 纤维化和胰岛素抵抗，而增加 SCAT 则显着阻止纤维化并改善 考虑到这一点，我们和其他人观察到 PLWH 的 SCAT 显着增加。 纤维化，这种反应在感染 SIV 的猕猴中复制出来，这促使我们想知道 PLWH 是否也有这种反应。 抑制米色脂肪细胞的生物发生，以及哪些因素决定了这一点。为此，我们最近确定了一个子集。 脂肪形成前体细胞 (APC) 表达控制 a 的特征标记 (Lin–: PDGFRa+: CD81+) 米色脂肪生物发生和 SCAT 纤维化之间的相互平衡具体来说，CD81+ APC 会引起。 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 这些数据强调了 SCAT 中 CD81+ APC 可能存在的有趣可能性。 我们还报道米色/棕色脂肪是支链脂肪的代谢库。 链氨基酸（BCAA），其循环水平与人类胰岛素抵抗激活有关。 棕色/米色脂肪生物发生可清除人体循环中的 BCAA；事实上，BCAA 清除是一种非侵入性的方法； 棕色/米色脂肪活性的指标然而，尚未评估 PLWH 中脂肪中 BCAA 使用的影响。 我们发现 CD81+ APC 维持正常 SCAT 功能的能力降低，这由 SCAT 反映出来 纤维化和 BCAA 清除受损，导致 PLWH 的胰岛素抵抗，扭转这种情况可能会改善 利用一组创新的 PLWH 和未感染对照（包括 MUO 患者）， 我们建议通过追求两个目标来检验这一假设，每个目标都将全面的人类研究与 在创新小鼠模型中进行机制研究 在目标 1 中，我们研究了 CD81+ APC 的丢失程度。 丰度、增殖能力或分化潜力可预测 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，我们探讨了脂肪。 BCAA 的清除作为 PLWH 中葡萄糖稳态的决定因素，并确定破坏的影响 米色/棕色脂肪 BCAA 对小鼠 SAT 纤维化和代谢健康的影响通过验证机械指数。 预测 MUO 的 SCAT 健康状况（CD81+ APC、纤维化、BCAA 清除），并利用该指数来改善 胰岛素敏感性，我们也许能够揭示延长感染者的代谢健康寿命的新方法。