Obesity and COVID-19: Role of Adipose Tissue

肥胖和 COVID-19：脂肪组织的作用

• 批准号: 10442684
• 负责人: TRACEY MCLAUGHLIN
• 金额: $ 19.68万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442684
• 关键词: 2019-nCoV; ACE2; Address; Adipocytes; Adipose tissue; COVID-19; Cardiac; Cells; Central obesity; Down-Regulation; Fatty acid glycerol esters; Fibrosis; Functional disorder; Goals; Heart; Human; Hypertension; Immune response; Impairment; Infection; Inflammation; Inflammatory Response; Injury; Intestines; Investigational Therapies; Kidney; Link; Liver; Metabolic syndrome; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Outcome; Pharmacology; Play; Predisposition; Proteins; Renin-Angiotensin System; Research; Risk; Risk Factors; Role; SARS-CoV-2 exposure; Viral; Viral Load result; Virus Diseases; Visceral; obese person; receptor; response; subcutaneous; treatment effect; vasoconstriction

PROJECT SUMMARY/ABSTRACT Obesity is a major risk factor for severe outcomes in Covid-19, exceeding the risk associated with type 2 diabetes and hypertension by 3-fold. The underlying reason is unknown. While obese individuals may have an impaired immune response or a predilection towards inflammation, hypertension, and cardiac decompensation due to underlying metabolic syndrome, we hypothesize that a more specific mechanism is at play: ACE2, the receptor for the spike protein on SARS-CoV-2 is highly expressed in subcutaneous and visceral adipose tissue, which may allow for viral entry and replication. Particularly in peri-organ fat depots, inflammation, vasoconstriction and fibrosis as a consequence of viral infection and subsequent downregulation of ACE2 may contribute to organ damage including heart, gut, liver, and kidney. As such, the goal of this project is to determine whether SARS-CoV-2 infects human adipocytes from subcutaneous (SAT), visceral (VAT), epicardial (EAT), and paracardial adipose tissue (PAT), whether infection incites inflammation, and whether pharmacologic compounds that target the renin-angiotensin system (RAS)/ACE2 alter infectivity and inflammation. 1. Assess the ability of SARS-CoV-2 to infect adipocytes and/or other resident cells in adipose tissue (SAT, VAT, EAT, PAT) 2. Profile the inflammatory response in adipose tissue cells exposed to SARS-CoV-2 3. Determine the ability of pharmacologic compounds that target RAS/ACE2 to inhibit infectivity and/or inflammation The results of this research will: 1) address a fundamental and critically-important question: does adipose tissue play a role in the link between obesity and COVID-19, via increased infection and/or inflammation; and 2) evaluate the effects of treatments targeting RAS/ACE2 that may mitigate infectivity and/or inflammation in adipose tissue.

项目摘要/摘要 肥胖症是Covid-19的严重结果的主要危险因素，超过了与2型糖尿病有关的风险 和高血压的3倍。根本原因是未知的。肥胖的人可能有障碍 免疫反应或偏向于炎症，高血压和心脏代偿作用。 潜在的代谢综合征，我们假设一种更具体的机制正在发挥作用：ACE2，受体的受体 SARS-COV-2上的尖峰蛋白在皮下和内脏脂肪组织中高度表达，这可能允许 用于病毒进入和复制。特别是在器官肥胖库中，炎症，血管收缩和纤维化作为一种 病毒感染的结果和随后的ACE2下调可能导致器官损伤 心，肠，肝脏和肾脏。因此，该项目的目标是确定SARS-COV-2是否感染了人类 皮下（SAT），内脏（增值税），心外膜（EAT）和心脏脂肪组织（PAT）， 感染是否会促进炎症，以及靶向肾素 - 血管紧张素的药理学化合物是否会引起炎症 系统（RAS）/ACE2改变感染性和炎症。 1。评估SARS-COV-2感染脂肪组织中脂肪细胞和/或其他居民细胞的能力（SAT，VAT， 吃，拍子） 2。介绍暴露于SARS-COV-2的脂肪组织细胞中的炎症反应 3。确定靶向RAS/ACE2抑制感染性和/或的药理化合物的能力 炎 这项研究的结果将：1）解决一个基本且至关重要的问题：脂肪组织会发挥作用吗 通过增加感染和/或炎症，在肥胖与共同-19之间的联系中的作用； 2）评估效果 靶向RAS/ACE2的治疗方法可能会缓解脂肪组织中的感染性和/或炎症。

项目成果

SARS-CoV-2 infection drives an inflammatory response in human adipose tissue through infection of adipocytes and macrophages.

• DOI: 10.1126/scitranslmed.abm9151
• 发表时间: 2022-12-07
• 期刊: SCIENCE TRANSLATIONAL MEDICINE
• 影响因子: 17.1
• 作者: Martinez-Colon, Giovanny J.;Ratnasiri, Kalani;Chen, Heping;Jiang, Sizun;Zanley, Elizabeth;Rustagi, Arjun;Verma, Renu;Chen, Han;Andrews, Jason R.;Mertz, Kirsten D.;Tzankov, Alexandar;Azagury, Dan;Boyd, Jack;Nolan, Garry P.;Schuerch, Christian M.;Matter, Matthias S.;Blish, Catherine A.;McLaughlin, Tracey L.
• 通讯作者: McLaughlin, Tracey L.