Molecular aspects of COVID-19 and its relationship with obesity and physical activity: a narrative review

Abstract BACKGROUND: Severe acute respiratory syndrome coronavirus 2 has several mechanisms of action related to inflammatory responses, especially in individuals diagnosed with obesity. This hyperinflammatory clinical profile resulting from the association between obesity and coronavirus disease 2019 (COVID-19) may be attenuated by regular physical activity. OBJECTIVE: The aim of this study was to review the evidence on the consequences of physical inactivity and physical activity on COVID-19 in patients with obesity. DESIGN AND SETTING: Narrative review at the Bahiana School of Medicine and Public Health in Salvador, Brazil. METHODS: We searched evidence on the association of COVID-19 with physical activity and obesity using the following keywords: “covid-19,” “physical activity,” and “obesity”. The databases used were MEDLINE (PubMed), ScienceDirect, and Virtual Health Library. Studies published from 2019 to 2021 and available in Portuguese, English, and Spanish were included. The final search was conducted on September 26, 2021. RESULTS: We identified 661 studies in the database, among which 71 were considered for inclusion in the narrative review of the molecular aspects of COVID-19 and its relationship with physical activity and obesity. CONCLUSION: This literature review enabled the perception of the relationship between the molecular mechanisms of COVID-19 and obesity. Regular physical activity had various benefits for the inflammatory condition of the studied population, highlighting moderate-intensity.

than 150 min per week and the attenuation of weight gain in adults, corroborating the recent World Health Organization update on PA recommendations during the COVID-19 pandemic. 7,8 PA seems to reduce the inflammatory state of individuals with obesity through molecular changes in the adipose tissue, attenuating the action of inflammatory mechanisms, based on the expression of proteins, such as peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), that favor mitochondrial biogenesis, and activation of molecular pathways, such as the AMP-activated protein kinase (AMPK) pathway, that, given increased enzymatic activity, act directly on lipid metabolism. 9,10 There are gaps in the literature regarding COVID-19 and its molecular mechanisms, to the detriment of the population diagnosed with obesity, relating to effective methods to alleviate the exacerbated responses to which these individuals are exposed, given the inflammatory mechanism of these two pathologies.

OBJECTIVE
The aim of this study was to review the evidence regarding the consequences of physical inactivity and exercise on  in patients with obesity. The search was performed on the informed database. Duplicate articles were removed and filtered, based on the inclusion criteria, using the following order: reading of the titles, abstracts, and full text. In addition to the search strategy, some articles were accessed manually from reference lists.

RESULTS
The results of the search and selection strategy are shown in the flowchart (Figure 1).

Inflammatory mechanisms of obesity
Obesity, a chronic disease associated with inflammatory responses, can develop owing to multiple factors, including genetic predisposition, emotional disorders, hormonal changes, and energy imbalance between high caloric intake and low caloric expenditure, resulting in the proliferation of excess adipose tissue. [11][12][13] This highly pro-inflammation compromises several metabolic mechanisms, such as glycemic regulation and beta-oxidation, and causes endothelial and vascular dysfunctions. 14 In general, the levels of several proteins and cytokines related to inflammatory responses are above the standards in obese individuals. A recent literature review identified elevated C-reactive protein levels (≥ 3 mg/L) in 14.4% of individuals with normal body mass index and 36% of obese individuals. 15 According to Zeyda and Stulnig, 16 the greater the amount of adipose tissue, the greater the secretion of interleukin (IL)-6, with visceral adipose tissue being the main factor responsible for the secretion of this cytokine, which has local and systemic mechanisms of action. In addition to visceral adipose tissue, IL-6 may originate in skeletal and smooth muscle tissue and endothelial, liver, and pancreatic cells. 14,17,18 Among various possible outcomes, the release of IL-6 from these structures results in the increased production of triacylglycerol by the liver, inhibition of lipase and hepatocyte insulin receptors, and, consequently, insulin resistance. 16,19 The positive correlation between IL-6 and C-reactive protein (CRP) levels results in an immunoregulatory function, as CRP is responsible for mediating the acute inflammatory response to aggressive agents and activating the complement system, which activates inflammatory processes and acts via the classical pathway, in which C proteins are linked to the target microorganism, exposing the activation sites of the system and subsequently generating the cleavage process of these components, ranging from C1 to C9, thereby allowing defense against aggressive agents, in parallel to antibodies. 20 Elevated CRP levels are also associated with cardiovascular and metabolic pathologies, such as type 2 diabetes mellitus. 15,21,22 Dai et al. 23 have highlighted tumor necrosis factor-alpha (TNFα) as a cytokine that also plays a crucial role in obesity. Although not primarily synthesized in adipocytes, the messenger ribonucleic acid for the production of TNF-α is present in adipose tissue, which is then used for TNF-α synthesis by macrophages. Thus, TNF-α plays an important role in adipose tissue, where the production of cytokines such as IL-6, cellular processes such as apoptosis, and vascular processes such as angiogenesis occur. 23 It has been suggested that a high body mass index is associated with higher levels of TNF-α in the systemic circulation. [24][25][26] Other important inflammatory markers are adipokines, cytokines secreted by adipose tissue, which affect several metabolic pathways, as their secretion results in an immune system response to the aggressor agent, releasing leukocytes in response to systemic inflammation. Thus, obesity, at the molecular level, may have a systemic inflammation origin and not only be caused by adipose tissue dysfunction. 27 Adipokines are also directly linked to vascular homeostasis; the microcirculation present in the adipose tissue can be compromised by the growth and increase in the number of adipocytes, resulting in deficient local and systemic circulation.
This creates the need for angiogenesis to avoid severe impairments, such as adipocyte necrosis and worsening of adipose tissue inflammation, induced by hypoxia in obese individuals. [28][29][30][31][32] Obesity and COVID-19 The mechanism of action of COVID-19 may be related to inflammatory immune responses caused by contact between the virus and pulmonary epithelium. Individuals with impaired immune responses, as well as those affected by chronic non-communicable diseases, have previous inflammatory conditions; thus, they are prone to complications caused by this infection, among whom individuals diagnosed with obesity are at greater risk. 33 In a recent literature review, Stefan et al. 34 identified that the risk of this infection worsening is greater in obese patients, especially in those with high levels of visceral fat. This occurs because visceral adipose tissue is one of the major factors responsible for the expression of inflammatory mediators related to obesity. 34 Moreover, excess adipose tissue, especially visceral adipose tissue, is associated with the greater presence of T cells with reduced immune response owing to metabolic dysregulation caused by obesity. This reduced immune response is linked to the decreased functional activation of CD4 and CD8 T cells and the presence of ACE2. 34,35 ACE, which is also expressed in adipose tissue, acts as a receptor for SARS-CoV-2 in a way that favors the maintenance of the inflammatory state in obese individuals and, consequently, increases the risk of serious outcomes. [35][36][37] Dysregulated immune responses to the virus tend to compromise other systems that were not previously infected owing to the presence of infected macrophages in the systemic circulation and impaired generation of antibodies, which cause immune suppression in infected obese individuals. 38 Immune dysregulation, which tends to occur in obese individuals affected by COVID-19, may be related to a phenomenon known as hypercytokinemia or "cytokine storm. " 39 However, Brandão et al. 40 have indicated that the initial immune response is very weak considering the high SARS-CoV-2 viral load, which justifies the excessive recruitment of cytokines. This mechanism of