Assessing the Impact of SARS-CoV-2 on Adipose Tissue Function and Glucose Homeostasis
NIH
WEILL MEDICAL COLL OF CORNELL UNIV
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. Public Health Relevance The deadly COVID-19 pandemic is underscored by the high morbidity and mortality rates seen in certain vulnerable populations, including patients with diabetes mellitus (DM) and obesity. Despite this well-known association, our understanding of how and why this occurs is lacking leading to an absence of specific therapies. In this proposal, we aim to test the mechanisms by which COVID-19 leads to adverse outcomes in diabetes mellitus and obesity with the goal of developing new therapies for patients with COVID-19.
Non-SBIR/STTR