








key: cord-329308-ipui7lo6
authors: Lim, Soo; Shin, Soo Myoung; Nam, Ga Eun; Jung, Chang Hee; Koo, Bo Kyung
title: Proper Management of People with Obesity during the COVID-19 Pandemic
date: 2020-06-30
journal: J Obes Metab Syndr
DOI: 10.7570/jomes20056
sha: 
doc_id: 329308
cord_uid: ipui7lo6

Since December 2019, countries around the world have been struggling with a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Case series have reported that people with obesity experience more severe coronavirus disease 2019 (COVID-19). During the COVID-19 pandemic, people have tended to gain weight because of environmental factors imposed by quarantine policies, such as decreased physical activity and increased consumption of unhealthy food. Mechanisms have been postulated to explain the association between COVID-19 and obesity. COVID-19 aggravates inflammation and hypoxia in people with obesity, which can lead to severe illness and the need for intensive care. The immune system is compromised in people with obesity and COVID-19 affects the immune system, which can lead to complications. Interleukin-6 and other cytokines play an important role in the progression of COVID-19. The inflammatory response, critical illness, and underlying risk factors may all predispose to complications of obesity such as diabetes mellitus and cardiovascular diseases. The common medications used to treat people with obesity, such as glucagon-like peptide-1 analogues, statins, and antiplatelets agents, should be continued because these agents have anti-inflammatory properties and play protective roles against cardiovascular and all-cause mortality. It is also recommended that renin–angiotensin system blockers are not stopped during the COVID-19 pandemic because no definitive data about the harm or benefits of these agents have been reported. During the COVID-19 pandemic, social activities have been discouraged and exercise facilities have been closed. Under these restrictions, tailored lifestyle modifications such as home exercise training and cooking of healthy food are encouraged.

ported that obesity is associated with the severity of COVID-19. [6] [7] [8] However, the features of COVID-19 in people with obesity have not been elucidated and it has not been determined whether obesity is an independent risk factor for susceptibility to infection with SARS-CoV-2 or the severity of COVID-19 or both.

We obtained data from a retrospective multicenter study in which all 28 of the first confirmed patients with COVID-19 in the Republic of Korea were enrolled. Five of these patients had a body mass index (BMI) >30 kg/m 2 (18%). 9 Zheng et al. 10 Table 1 .

During the COVID-19 pandemic, dietary patterns have changed to include increased reliance on delivered foods, and access to healthy food options has diminished. 11 Delivered foods are mostly fast foods, such as pizza, hamburgers, fried chicken, and sugar-sweetened beverages or carbonated soda. 12 These items are probably more obesogenic than home-cooked foods. 13 Increased consumption of these foods is associated with increased risk of obesity and DM. 14, 15 People with obesity or who are overweight are reported to be less active. 16, 17 In addition, during the COVID-19 pandemic, community health centers, gyms, swimming pools, and parks have been closed by law in many countries as part of their quarantine strategy.

These changes in the food and social environments may have contributed to an increase in body weight in people with obesity as well as in the general population. 

In addition to old age, smoking, and underlying CVD and DM, obesity is considered to be a risk factor for COVID-19 ( Fig. 1) .

Several factors may affect the relationship between COVID-19 and obesity. Studies have reported that the immune system is frequently compromised in people with obesity and that COVID-19 affects the immune system, and these links may also worsen the complications of obesity. 55, 56 Of note, an excess production of interleukin 6 (IL-6) and other cytokines released in response to COVID-19 can induce a "cytokine storm" (hypercytokinemia), which is believed to increase the fatality of COVID-19. 57 COVID-19 can also progress to severe respiratory illness and hypoxia, which may predispose people to being immobile and to gaining weight.

Obesity represents a state of chronic low-grade inflammation.

Hyperplastic or hypertrophied adipose tissues directly secret various inflammatory products ( Fig. 1) , such as inflammatory cytokines, transforming growth factor-β, adipokines, monocyte chemoattractant protein 1 (MCP1), C-X-C motif chemokine ligand 5, hemostatic proteins, proteins affecting blood pressure, and angiogenic molecules. 58, 59 The main inflammatory cytokines derived from adipose tissues are tumor necrosis factor α (TNF-α), IL-6, and IL-1. Increased TNF-α level in people with obesity reflects a . *Possibly related to the closing of public and private facilities such as community health centers, gyms, swimming pools, parks, and schools on the basis of quarantine strategies during the COVID-19 pandemic; † Possibly related to the quarantine policies and financial effects during the COVID-19 pandemic. Socioeconomic factors: ↓physical activity, 40 ↓opportunities for exercise, 41 ↑unhealthy food consumption. 11 Systemic factors: ↑inflammatory cytokine production, 42-44 compromised immune system, 45 ↑insulin resistance, 46 impaired glucose regulation, 46 ↓cardiac function, 47 ↓tissue perfusion, 48 activation of renin-angiotensin system. 49, 50 Biomechanical factors: ↓lung compliance, 51 ↓functional residual capacity, 51 ↑airway hyperresponsiveness, 52 ↑small airway collapse, 52 ↑esophageal and gastric pressure, 53 ↑obstructive sleep apnea, 54 ↑hypoxemia. 54 A cumulative effect of chronic inflammation and hypercytokinemia seems to bring about a hyperinflammatory response through macrophage active syndrome, especially in patients with severe COVID-19 (Fig. 2) . 44 Inflammation subsequently leads to hypoxia and ischemia, which results in an oxidative stress state involving release of inflammatory proteins and reactive oxygen species that impair mitochondrial function. As a result, protein synthesis by hypertrophic and hypoxic white adipocytes is altered toward the production of cytokines and other inflammatory proteins, which may lead to metabolic disease. 61, 62 A vicious cycle between elevated release of cytokines and a state of increased metabolic inflammation, which leads to cytokine storm, occurs in patients infected with SARS-CoV-2 (Fig. 2 ). In patients with COVID-19, cytokine storm has been proposed to be the cause of the multiorgan failure in patients with severe disease. 63, 64 For example, hyperglycemia was reported in 51% of patients with SARS-CoV-2 infection. 65 Hyperglycemia or type 2 DM, which is closely associated with obesity, has been suggested as an independent predictor of poor prognosis in patients with SARS-CoV-2. 66 Several mechanisms have been proposed to explain how SARS- CoV-2 infection induces inflammation and promotes insulin resistance (Fig. 2 ). 46 Patients with COVID-19 exhibit increased production and secretion of inflammatory markers, such as C-reactive protein (CRP), D-dimer, ferritin, and IL-6. 67 In general, virus infection increases IL-6 levels and this increase is associated with increased risk of diabetic complications. 75 Given its proinflammatory role in innate immunity, IL-6 level may correlate with disease severity and a procoagulant profile. 76 By increasing oxidative stress, IL-6

can damage proteins, lipids, and DNA, and this damage may alter the organism's structure and function. Viral-induced production of IFN-γ by natural killer cells causes insulin resistance in myocytes by downregulating insulin receptor transcription, thus causing insulin resistance. 46

The mechanisms linking the poor prognosis of COVID-19 with obesity overlap with the pathways that regulate immune function Hyperinsulinemia increases antiviral immunity through direct stimulation of CD8 + effector T-cell function. In prediabetic mice with hepatic insulin resistance caused by diet-induced obesity, infection resulted in loss of glycemic control. 46 Therefore, upon encountering pathogens, the immune system transiently reduces insulin sensitivity of skeletal muscle to promote antiviral immunity and induce hyperinsulinemia, which result in glucose intolerance.

Taken together, these findings suggest that obesity is associated with accelerated immune system aging and/or dysregulation and that these changes may relate indirectly to the COVID-19 prognosis. The immune modulation induced by obesity may be important to the susceptibility and severity of COVID-19 (Fig. 2) .

The renin-angiotensin system (RAS) appears to be activated in people with obesity. 49, 50 Normally, when blood flow decreases to the kidneys, the juxtaglomerular cells of the kidneys release renin, which activates the RAS. 82 In obesity, there is inappropriate activation of the RAS in the context of increased sodium intake, sodium/ water retention, central blood volume, and blood pressure (Fig. 1) . 49 This metabolic dysregulation is associated with the expansion in visceral adipose tissue content, which leads to increased production of angiotensinogen (up to 30% of circulating angiotensinogen) and

possibly elevated plasma renin activity. 49, 50 Massiera et al. 83 showed that angiotensinogen-deficient mice exhibit impaired weight gain, which supports the association between obesity and the RAS.

A large amount of visceral adipose tissue induces release of insulin, which activates angiotensin type 1 receptors and influences the release of TNF-α and IL-6 from adipocytes, resulting in activation of the RAS pathway. 84 Of note, the organ involvement of SARS correlates with the organ expression of ACE2. In addition, the localization of ACE2 expression in the endocrine pancreas suggests that coronavirus enters islets using ACE2 as its receptor and damages islets, which leads to hyperglycemia. 38 These data suggest that the RAS may be involved in the association between obesity and COVID-19. 86 The facial features of people with obesity may differ from those without, 87, 88 and it may be more difficult to find the right mask size for people with obesity.

Social distancing is recommended as the most effective way of slowing the spread of COVID-19. In a physically identical space, larger objects will be placed closer to each other. For this reason, it may be difficult for people with obesity to maintain social distance from other people, which may increase the risk of exposure to the virus. People with obesity tend to spend less time in work, recreation, and rest activities, and more time in activities of daily living than do those without obesity (Fig. 1) . 41 

Glucagon-like peptide-1 (GLP1) analogues have an anti-inflammatory effect. For example, the mRNA levels of GLP1 receptors are downregulated in monocytes that have differentiated into macrophages. 89 Treatment with exendin-4 decreases monocyte/macrophage accumulation and mRNA expression of inflammatory markers such as TNF-α and MCP1 in the arterial wall of ApoE -/mice. 90 Overexpression of GLP1 in balloon-injured vessels reduces monocyte infiltration and improves reendothelialization, which contribute to reduced neointimal formation. 91 In mice fed a high-fat diet, treatment with liraglutide (30 μg/kg twice daily) decreases TNF-α expression and translocation of its downstream signal NF-κB-p65 92 and adhesion of human monocytes to TNF-α-activated human endothelial cells. 92 In vitro MCP1 expression and NF-κB-p65 translocation also decrease significantly after GLP1 treatment. 91 GLP1 analogues can shift the polarization profile of macrophages from M1 toward M2, 93 supporting the anti-inflammatory properties of GLP1 analogues.

Liraglutide therapy has an anti-inflammatory effect by increasing nitric oxide production in endothelial cells. 93 Liraglutide and semaglutide treatment reduce the development of atherosclerosis through mechanisms involving inflammatory pathways in ApoE -/and LDL receptor -/mice. 94 In humans, GLP1 and GLP1 analogues have been shown to be beneficial for the treatment of chronic inflammatory diseases such as nonalcoholic fatty liver disease, 95 atherosclerosis, 91 and neurodegenerative disorders. 96 Taken together, these findings suggest that GLP1 analogues have a protective role against atherosclerosis that is mediated by a dampening of the inflammatory pathways. 97 Therefore, alleviation of inflammatory processes in the vascular system by these agents is a rationale for the recommendation to prescribe GLP1 analogues during the CO-VID-19 pandemic. 102 In one in vitro study, sitagliptin, vildagliptin, and saxagliptin could not block the entry of coronaviruses into cells. 103 Although ACE2 is the main receptor for SARS-CoV-2, a recent modeling study did not rule out its interaction with CD26 or DPP4. 103 At present, there is insufficient evidence either for or against the use of DPP4 inhibitors in patients with DM and COVID-19. 104

The physiological role of ACE2 counter-regulates the renin-angiotensin-aldosterone system (RAAS). 105 Independent of the RAAS, ACE2 also regulates intestinal amino acid homeostasis and the gut microbiome. 106 In COIVD-19, ACE2 on the respiratory epithelium serve as a main entry of SARS-CoV-2. 107 Interaction of SARS-CoV with ACE2 is initiated via trimers of the SARS spike protein, which extends into a hydrophobic pocket of the ACE2 catalytic domain that is independent of its peptidase activity. 108 ACE2 is highly expressed in the lung as well as in the heart, endothelium, kidney, and gastrointestinal tract, and the tissue distribution of ACE2 overlaps with the tissue tropisms of SARS-CoV-2. 109 This means that ACE2 expression may be implicated in the severe illness caused by COVID-19. Higher expression of ACE2 in patients with hypertension and CVD has been postulated as a factor that increases the susceptibility to SARS-CoV-2. 108 By contrast, there is evidence that ACE2 may have a beneficial role in COVID-19. Both SARS-CoV infection and challenge with recombinant SARS spike protein trigger marked downregulation of ACE2 expression in the lung. 110 Downregulation of ACE2 results in susceptibility of lung injury 111 and unopposed RAAS activation. 112 In animal models, elimination of ACE2 was associated with severe lung injury, which could be recovered by recombinant ACE2 protein. 111 In addition, ACE2-knockout mice exhibited cardiac dysfunction, which could be reversed by concomitant deletion of ACE. 113 Reduced ACE2 expression in cardiac injury has been confirmed in SARS infection 114 and myocardial infarction. 111 Given that the involvement of the cardiopulmonary system is a key factor for the severity of COVID-19, ACE2 may play a role in the prognosis of COVID-19.

People with obesity often also develop hypertension or heart failure. 112 A large multicenter study has confirmed that hypertension can increase the risk of severe COVID-19 by as much as 1.7 times. 19 RAAS inhibitors are the mainstay for treatment of hypertension and heart failure. Because RAAS inhibitors can increase the tissue expression of ACE2 in animal models, 115 RAAS inhibitors may increase the susceptibility to COVID-19 and its severity after exposure to SARS-CoV-2. 108 However, all classes of antihypertensive medication including RAAS inhibitors are not associated with a substantial increase in the risk of severe illness in COVID- 19. 116 The effect of RAAS inhibitors on ACE2 level or activity in human studies is controversial. Generally, ACE inhibition does not affect ACE2-directed angiotensin II metabolism, 117, 118 and only specific RAAS inhibitors appear to increase the ACE2 level. 119 

Hydroxymethylglutaryl-CoA reductase inhibitors or statins have anti-inflammatory properties. In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin trial, rosuvastatin reduced the relative risk of major cardiovascular events by 44% in people without hyperlipidemia but with elevated high-sensitivity CRP level. 126 In a viral pneumonia mouse model, simvastatin directly modulated antiviral inflammatory responses in lung tissues. 127 In that study, simvastatin treatment attenuated airway inflammation, such as RANTES (regulated on activation, normal T-cell expressed and secreted) expression and neutrophil recruitments. 127 Rosuvastatin therapy also has additional benefits including anti-inflammatory effects beyond the lipid-lowering property, which suggests that this drug has pleiotropic effects. 128 These data support the favorable effects of statins on respiratory diseases. 129 Statin therapy should be continued during the COVID-19 pandemic if there is no definite contraindication.

During the COVID-19 pandemic, people with obesity should maintain a heathy lifestyle. Regular exercise is essential to maintaining immunity. 130 Healthy eating is also crucial for strengthening the immune system and reducing inflammation. 130 People with obesity who experience symptoms such as cough, sputum, fever, or a sudden increase in blood glucose level should consult their physician immediately. The clinical guidelines for the management of obesity-related disorders should be followed closely. Health-care providers should make sure that their patients with obesity do not stop taking antiobesity agents, particularly GLP1 analogues, or medications for obesity-related disorders such as statin and ACE inhibitors or angiotensin receptor blockers, provided there is no contraindication to these patients taking these agents.

In conclusion, COVID-19 is a global pandemic and may pose considerable health hazard, especially for people with obesity. Obesity is a risk factor for poor outcomes of viral infection because of the deleterious effects of obesity on the immune system, which can lead to mortality in people with obesity with COVID-19. During the COVID-19 pandemic, it is important for people with obesity to maintain a healthy lifestyle, and their medications should be adjusted properly. Close monitoring of patients with obesity is required because of the restrictions imposed by the quarantine policies on physical activity and healthy eating. The optimal management strategy for these people warrants further investigation.

The authors declare no conflict of interest.

Study concept and design: SL; acquisition of data: SL and SMS; analysis and interpretation of data: SL; drafting of the manuscript: all authors; critical revision of the manuscript: all authors; administrative, technical, or material support: SL and SMS; and study supervision: SL.

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