Immunometabolic Dysregulation at the Intersection of Obesity and COVID-19

Abstract

Obesity prevails worldwide to an increasing effect. For example, up to 42% of American adults are considered obese. Obese individuals are prone to a variety of complications of metabolic disorders including diabetes mellitus, hypertension, cardiovascular disease, and chronic kidney disease. Recent meta-analyses of clinical studies in patient cohorts in the ongoing coronavirus-disease 2019 (COVID-19) pandemic indicate that the presence of obesity and relevant disorders is linked to a more severe prognosis of COVID-19. Given the significance of obesity in COVID-19 progression, we provide a review of host metabolic and immune responses in the immunometabolic dysregulation exaggerated by obesity and the viral infection that develops into a severe course of COVID-19. Moreover, sequela studies of individuals 6 months after having COVID-19 show a higher risk of metabolic comorbidities including obesity, diabetes, and kidney disease. These collectively implicate an inter-systemic dimension to understanding the association between obesity and COVID-19 and suggest an interdisciplinary intervention for relief of obesity-COVID-19 complications beyond the phase of acute infection.

Keywords: COVID-19; immunometabolism; immunopathy; metabolic disorder; obesity.

Figure 1

Immunometabolic proxies underlying the association between obesity and the severe course of COVID-19. Studies have associated the propensity of severe COVID-19 manifestation in patients with obesity and relevant metabolic comorbidities. The emerging theme indicates the immuno-pathological exaggeration of predisposed immuno-metabolic disorder (indicated in the circles, especially the overlapped region on the left) in the obese COVID-19 patients. This predisposed immunometabolic disorder magnifies, locally and systemically, the virus pathogenicity and relevant immunopathies leading to more severe COVID-19 manifestations. COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Created with BioRender.com.

Figure 2

Obesity-originated immunometabolic diversion underlying the association between obesity and the severe course of COVID-19 manifestations. Studies about obesity and associated metabolic disorders show the following: (1) increases of local and plasma mediators including leptin, insulin, glucose, lipids, and particularly various proinflammatory cytokines/leukocytes underlying relevant metabolic stress and inflammatory status accompanying excessive deposit of adipose tissues and development of metabolic disorders; (2) high incidences of cell senescence and death of adipocytes and associated epithelial and mesenchymal cells, which amplify proinflammatory signaling, dysregulate IFN-mediated antiviral response, and induce tissue expression of molecules facilitating SARS-CoV-2 susceptibility; (3) compromised or shifted antiviral immunity in both innate and adaptive arms; (4) respiratory obstruction resulting in hypoxia-mediated immune impairment; and (5) imbalance prone to autoimmune and thrombotic response. Arrowheads indicate increase (upward red) or decrease (downward green) of following molecular markers. Upward ball-head symbol ascribing abnormal chemotaxis and activation on leukocytes by obesity. ACE2, angiotensin converting enzyme 2; CCL, CC type chemokine ligand; CXCL, CXC type chemokine ligand; IFN, interferon; IFITM, interferon-induced trans-membrane proteins; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; p16 and p21, cellular senescence marker protein 16 and 21; TMPRSS2, transmembrane Serine Protease 2; TNF, tumor necrosis factor.

Figure 3

The virus–immune system interaction and relevant immunometabolic dysregulation underlying the association between obesity and the severe course of COVID-19. SARS-CoV-2 is notorious for its broad tissue tropism, including susceptibility that has been demonstrated in the airway, lung, intestine, kidney tubule, pancreatic duct, blood vessel, neuron, and adipocyte cells, implicating metabolic and immune disruption caused by direct viral infections in multiple systems. Studies indicate an extensive virus-immune system interaction at both innate and adaptive immune levels, with emphasis on the viral antagonism against the antiviral IFN system, hyper-inflammation incited by massive cell death upon immunopathies induced by the virus–host interaction, as well as various disruptions in adaptive immunity per T-cell- and B-cell-mediated responses. Some metabolic disruption of lipid biosynthesis has also been correlated to COVID-19 progression, but its long-term effect on the development of metabolic disorders in convalescent patients warrants further studies. PANoptosis, massive inflammatory cell death including Pytoptosis, Apoptosis, and Necroptosis. Other abbreviations are as listed in Figure 2 legend.