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 肥胖是新冠肺炎严重预后的主要风险因素，超过了与2型糖尿病相关的风险 高血压增加3倍。根本原因尚不清楚。而肥胖的人可能会有一个受损的 免疫反应或倾向于炎症、高血压和心脏失代偿 在代谢综合征的基础上，我们假设有一个更特定的机制在起作用：ACE2，即血管紧张素转换酶受体 SARS-CoV-2上的刺突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。尤其是在器官周围脂肪堆积、炎症、血管收缩和纤维化方面 病毒感染和随后下调ACE2的后果可能导致器官损害，包括 心脏、肠道、肝脏和肾脏。因此，这个项目的目标是确定SARS-CoV-2是否会感染人类 来自皮下(SAT)、内脏(VAT)、心外膜(EAT)和心旁脂肪组织(PAT)的脂肪细胞， 感染是否会引发炎症，以及靶向肾素-血管紧张素的药物化合物是否 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/或其他驻留细胞的能力(SAT、VAT、 吃吧，帕特) 2.SARS-CoV-2对脂肪组织细胞炎症反应的影响 3.确定靶向RAS/ACE2的药物化合物抑制感染性和/或 炎症 这项研究的结果将：1)解决一个基本和至关重要的问题：脂肪组织是否在 通过增加感染和/或炎症，在肥胖和新冠肺炎之间的联系中发挥作用；以及2)评估影响 针对RAS/ACE2的治疗方法可以减轻脂肪组织中的传染性和/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.