Assessing the Impact of SARS-CoV-2 on Adipose Tissue Function and Glucose Homeostasis

评估 SARS-CoV-2 对脂肪组织功能和血糖稳态的影响

• 批准号: 10682138
• 负责人: James C Lo
• 金额: $ 69万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682138
• 关键词: 2019-nCoV; Acute; Adipocytes; Adipose tissue; Attenuated; Automobile Driving; Autopsy; Beta Cell; Biochemical; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 susceptibility; Cell physiology; Cells; Circulation; Cytometry; Data; Defect; Diabetes Mellitus; Disease; Endocrine Glands; Experimental Models; Failure; Fatty acid glycerol esters; Functional disorder; Genes; Goals; Hamsters; Health; Homeostasis; Hormones; Hyperglycemia; IRF3 gene; Image; Immunity; Impairment; Individual; Infection; Inflammatory; Insulin; Insulin Resistance; Interferons; Length of Stay; Long COVID; Maps; Mechanical ventilation; Metabolic; Metabolic Diseases; Modeling; Molecular; Morbidity - disease rate; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathogenesis; Pathology; Pathway interactions; Patients; Physiological; Play; Recovery; Role; SARS-CoV-2 infection; SARS-CoV-2 variant; Sampling; Specimen; Testing; Thinness; Virus Replication; Vulnerable Populations; adipokines; adiponectin; adverse outcome; aged; blood glucose regulation; cell type; combat; comparison control; coronavirus disease; follow-up; glucose metabolism; glucose tolerance; impaired glucose tolerance; in vivo; insulin secretion; insulin sensitivity; mortality; mouse model; novel; novel therapeutics; post SARS-CoV-2 infection; preservation; programs; public health relevance; receptor; symptom treatment; trait

Project Summary/Abstract COVID-19 has proven to be a metabolic disease resulting in adverse outcomes disproportionally afflicting individuals with diabetes or obesity. Patients infected with SARS-CoV-2 and hyperglycemia suffer from longer hospital stays, increased need for mechanical ventilation and mortality compared to those without hyperglycemia. We found that insulin resistance rather than beta cell failure is the predominant cause of hyperglycemia in acute COVID-19. The insulin sensitizing hormone adiponectin is diminished in the circulation of COVID-19 patients compared to controls. Furthermore, we demonstrate that SARS-CoV-2 can directly infect adipocytes. Importantly, we find replicating virus in adipose tissues of both autopsy samples from COVID-19 patients and in mouse and hamster experimental models of SARS-CoV-2 infection. Together these data suggest that SARS-CoV-2 triggers adipose tissue dysfunction to drive insulin resistance and adverse outcomes in acute COVID-19. In this proposal, we seek to follow up on these studies and assess the mechanisms driving adipose tissue dysfunction in acute and recovered models of COVID-19. We will pursue the following specific aims: 1. Assess the impact of acute SARS-CoV-2 infection on glucose homeostasis in obese and non-obese mice. 2. Map the spatiomolecular interactions and dissect the molecular mechanisms of SARS-CoV-2 infection in adipose. 3. Determine the long-term glycometabolic consequences of SARS-CoV-2 infection. The overall goal of these studies is to assess how COVID-19 can drive adipose tissue dysfunction and hyperglycemia and will shed light on novel targets to combat metabolic complications induced by COVID-19.

项目概要/摘要 COVID-19 已被证明是一种代谢性疾病，会导致严重影响患者的不良后果 患有糖尿病或肥胖症的人。感染 SARS-CoV-2 且患有高血糖的患者会遭受更长时间的痛苦 与没有机械通气的患者相比，住院时间、机械通气需求增加和死亡率增加 高血糖。我们发现胰岛素抵抗而不是β细胞衰竭是导致糖尿病的主要原因 急性 COVID-19 中的高血糖。胰岛素增敏激素脂联素在循环中减少 COVID-19 患者与对照组的比较。此外，我们证明 SARS-CoV-2 可以直接感染 脂肪细胞。重要的是，我们在 COVID-19 尸检样本的脂肪组织中发现了病毒复制 患者以及 SARS-CoV-2 感染的小鼠和仓鼠实验模型。这些数据共同表明 SARS-CoV-2 会引发脂肪组织功能障碍，从而导致胰岛素抵抗和急性期不良后果 新冠肺炎。在本提案中，我们寻求跟进这些研究并评估驱动脂肪的机制 COVID-19 急性和恢复模型中的组织功能障碍。我们将追求以下具体目标： 1. 评估急性 SARS-CoV-2 感染对肥胖和非肥胖小鼠葡萄糖稳态的影响。 2. 绘制空间分子相互作用图并剖析 SARS-CoV-2 感染的分子机制 脂肪。 3. 确定 SARS-CoV-2 感染的长期糖代谢后果。总体目标 这些研究的目的是评估 COVID-19 如何导致脂肪组织功能障碍和高血糖，并将 揭示了对抗 COVID-19 引起的代谢并发症的新靶标。