Implications of engaging in regular exercise and reducing sedentary behavior during a global pandemic: An immunometabolic perspective in patients with obesity and type 2 diabetes

Many reports showed a dramatic decrease in the levels of physical activity during the current pandemic of SARS-COV-2. This has substantial immunometabolic implications, especially in those at risk or with metabolic diseases including individuals with obesity and Type 2 diabetes. Here we discuss the route from physical inactivity to immnometabolic aberrancies; focusing on how insulin resistance could represent an adaptive mechanism to the low physical activity levels and/or high energy intake and on how such an adaptive mechanism could derail to be a pathognomonic feature of metabolic diseases creating a vicious circle of immune and metabolic aberrancies. We provide a theoretical framework to the severe immunopathology of COVID-19 in patients with metabolic diseases. We finally discuss the idea of exercise as a potential adjuvant against COVID-19 and emphasize how even interrupting prolonged periods of sitting with short time breaks of very light activity could be a feasible strategy to limit the deleterious effects of sedentary behavior.


Introduction
The world is going through tough time due to the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) pandemic. Since declared a pandemic by the World Health Organization (WHO) on March 11, 2020, home lockdown and social distancing have become the new standards of our daily life to limit the virus spread. These measures while important for containing the virus, they may have exacerbated an old pandemic -physical inactivity [1].
Moreover, even though many countries start to reopen progressively, individuals who are vulnerable to the severe forms of novel Corona virus disease (COVID-19) may prefer to not risk themselves and may avoid crowded places including physical activity facilities in the absence of viable vaccines.
Physical inactivity is considered the fourth leading cause of death by the WHO, and is fuelling the risks of metabolic diseases, including obesity and type 2 diabetes (T2D) [2].
Besides being a root cause of metabolic diseases, physical inactivity may have more profound deleterious effects on those with pre-existing chronic metabolic conditions [3]. Therefore obesity and T2D patients may pay high prices by not being active during this global pandemic.
Here we highlight the deleterious effects of physical inactivity on glucose metabolism, and how this may lead to metabolic and immune aberrancies. We discuss a hypothetical scenario of the immunopathology of COVID-19 in patients with obesity and T2D and how the immuno-metabolic dysregulations, characterizing these diseases, may perturbate immune defenses, leading therefore to poor COVID-19 prognosis. We finally provide a theoretical framework on how exercise by its anti-inflammatory effects may prevent the severe complications of COVID-19 and how even reducing sedentary time by very light physical activity may help by reducing metabolic derangements.

On the ruins of two pandemics: the road from couch to metabolic and immune aberrancies
Data from activity trackers showed a dramatic decrease in step counts ranging from 7-38% in European countries during the early weeks of the pandemic [4,5]. Similarly, an Italian study showed a significant decrease in weekly energy expenditure and that overweight individuals had the lowest levels of physical activity during quarantine [6]. This may have serious health implications since time spent sitting is now considered an independent risk factor for all cause mortality even after adjusting for physical activity levels [7]. As such time spent sitting seems to have deleterious effects even in those meeting the current physical activity guidelines. energy intake was matched to energy expenditure. However, short term decrease in insulin sensitivity is more and more considered as a physiological defense to divert excess nutrients from tissues with limited storage capacity (i.e. skeletal muscle and liver) to adipose tissue with almost unlimited storage capacity -a physiological response to prevent glucolipotoxicity [26,27]. In line with this, Dirks, Wall [28] showed that 7 days of bed rest does not result in ectopic fat deposition -a hallmark of pathologic insulin resistance -while in the same time cause insulin resistance. Animal model studies of physical inactivity confirm also these findings [29]. This is, perhaps, best reflected by the fact that healthy individuals may to some extent tolerate the effects of physical inactivity and restore their insulin sensitivity levels once returned to habitual physical activity [22]. On the long run, though, it is believed that the chronic storage of excess nutrients in adipose tissue, resulting from low levels of physical activity and/or excess food intake, leads to adipocytes enlargement (hypertrophy) and multiplication (hyperplasia) and therefore to increased fat mass [30,31]. This is believed to be the critical point that initiates adipose and systemic immune and metabolic aberrancies (See Figure 1) lipid engorged adipocytes express a stress phenotype characterized by activation of inflammatory signaling pathways that regulate stress-induced cell death. Cell death promotes macrophages and T cells recruitment [32,33], polarization of macrophages and T cells towards an inflammatory phenotype [34], blunted B cell antigen production, and expression of a more pro-inflammatory cytokines repertoire [35,36]. Among the pro-inflammatory cytokines, tumor necrosis factor (TNF-α) was the first to be reported to interact with metabolism, and to blunt insulin action through insulin receptor substrate phosphorylation at serine residues leading thereafter to adipose and systemic insulin resistance [37,38]. Figure 1. Obesity and its associated metabolic and immune abnormalities. Adipose tissue expansion in obesity is accompanied by an increase in size and number of adipocytes. This drives a shift of local immune cells homeostasis towards a more pro-inflammatory phenotype, which communicates insulin resistance at a systemic level through proinflammatory mediators. Importantly this immuno-metabolic complications create a feed forward loop that compromises the cardiometabolic health; leading to cardio-metabolic diseases, and compromises the immune system; leading to increased infection risks.
The discovery of TNF-α; as a mediator of insulin resistance, was one of the earliest clues of metabolic and immune connection that paved the way for the birth of the Immunometabolism field [39]. The birth of this field led to the recognition that besides the metabolic component, obesity has an inflammatory component; featured by the subclinical elevations of many proinflammatory cytokines and the polarization of many of the immune cells towards an inflammatory phenotype [39]. Also of importance, studies in this field revealed that the elevated nutrients characterizing obesity and its associated complications are recognized by innate immune sensors, specifically pattern recognition receptors, and are a well documented trigger of inflammation [40,41]. For example Toll like receptor (TLR); a pattern recognition receptor, is known to be activated by saturated fatty acids (SFA) [40] and glucose [42], which leads to the activation of inflammatory signaling pathways and expression of proinflammatory cytokines. Moreover, Palmitate, a SFA, activates NLPR3 inflammasome, leading to IL-18 and IL-1β production in hematopoietic cells, and this blunts insulin signaling, impairs glucose tolerance and insulin sensitivity in multiple other tissues [43]. Finally, the mounting of an effective immune response to defend the host, requires glucose to be directed towards immune cells, and this involves peripheral insulin resistance [44,45].
At this point, it is important to distinguish between physical inactivity-induced insulin resistance and the insulin resistance featuring chronic diseases: physical inactivity-induced insulin resistance, is an adaptive mechanism, and is not accompanied by inflammation [46,47], however; metabolic diseases-induced insulin resistance is a combination of both inflammatory and metabolic aberrations. Therefore patients with metabolic diseases, with an already abrogated immunometabolic profile may be particularly vulnerable to physical inactivity. In support of this notion, a study demonstrated in overweight aged pre-diabetic individuals that two weeks of step reductions impaired glucose control, insulin sensitivity and inflammatory markers (TNF-α, IL-6, CRP) [3]. Importantly these effects did not resolve two weeks after returning to the pre-step reduction phase, which is in contrast with the findings in healthy adults and aged individuals [22,47] In conclusion, this overlap between immune and metabolic pathways determines in metabolic diseases a feed forward loop of complications between inflammation and insulin resistance (see figure 1), which alters metabolic health and drives obesity-associated cardiometabolic complications. It is noteworthy that the contribution of defective immunometabolic profile in metabolic diseases is less well characterized in the context of infections, and could play an important role in the increased susceptibility and the bad prognosis in infectious diseases [48][49][50].

COVID-19: A nutrient perspective
The presence of chronic diseases, including obesity and T2D, has been associated with the development of the severe form of . Severe COVID-19 include acute respiratory distress syndrome (ARDS), septic choc, multiple organ failure and death [55]. The severity of the disease is usually accompanied by elevated inflammatory cytokines: IL-2R, IL-10, IL-6, IL-8 and TNF-α, reminiscent of the cytokines releasing syndrome [53,56,57]. This is also seen in SARS-COV-1, which shares 80% homology with SARS-COV-2 [58].
Importantly, ARDS, during SARS-COV outbreak was shown to occur despite reductions in viral load, suggesting altered host response rather than viral virulence.
In a retrospective multicentred cohort of 7,336 confirmed COVID-19 cases with or without diabetes in Hubei Province, China, diabetics had significantly higher mortality rate and higher multi-organ injury [59]. In this cohort, controlled blood glucose levels correlated with improved outcomes and were associated with markedly lower mortality rate compared to uncontrolled glucose status. In the whole cohort, as well as in the diabetic group, lymphocytopenia, neutrocytosis, and increased circulating IL-6 correlated with blood glucose.
The group with controlled blood glucose showed lower lymphocytopenia, lower neutrocytosis, and lower IL-6 levels, all of which correlated with the controlled glucose status [59], suggesting an interaction between glucose and immune cells.
Pathogen associated molecular pattern (PAMPs) are recognized by the innate microbial sensors, called pathogen recognition receptors (PRRs). In the case of SARS-COV-2, the genomic viral RNA could be recognized by Toll like receptors, NOD-like receptors or RIG-I-like receptors [60,61]. This recognition activates downstream signaling and promotes pro-inflammatory cytokines production in a nuclear factor kappa B (NF-B) and in an interferon regulatory factor (IRF) 3/7 dependent manner [61,62]. Importantly, IRF 3/7 are known to upregulate Type I interferon (IFN-I) production leading to the activation of interferon stimulated genes and to the secretion of many pro-inflammatory which constitutes an early first line of innate immune defense that interferes with viral replication [63]. In an elegant study, Hu, Xia [64] investigated the effect of acute and short term effects of hyperglycemia on IFN-I production and signaling by peripheral blood mononuclear cells (PBMC). The study consisted in incubation of PBMC with different glucose concentrations and Polyinosinic:polycytidylic acid (polyI:C) stimulation, with polyI:C being a double stranded RNA (dsRNA) that stimulate IFN-I via Toll like receptor (TLR) 3. The authors demonstrated that blood glucose levels differentially affect IFN-I production and signaling in both acute and short term conditions: moderately elevated glucose (8 mmol) promoted IFN-I production, however, highly elevated glucose levels (24 mmol) impaired it. These acute and short term results have important implications; as outlined earlier, the inflammatory response is glucose dependent, therefore acute moderate elevations in blood glucose may boost the immune response against pathogens, in part by increased IFN-I production. Further confirming this notion is that acute incubation with moderately elevated glucose and polyI:C increased CD169, a sensitive IFN-I signaling marker, expression on PBMC, while acute incubation with highly elevated glucose and polyI:C decreased CD169 expression [64].
Therefore by suppressing IFN-I, high glucose levels may promote viral replication and persistence. Furthermore, high glucose levels, from the latter study, also increased many cytokines, including; IFN-γ, TNF-α, IL-1β, IL-6, IL-8, . Importantly most of these cytokines were reported to be elevated in severe COVID-19 patients, suggesting that hyperglycemia could contribute to the immunopathology of 57].
Many mechanisms by which hyperglycemia reprogram leucocytes to an inflammatory profile: for example advanced glycation end products (AGEs) mediate the M1 program of macrophages by the activation of NF-B pathway, which promote IL-6 and TNF-α expression [65]. Similarly, upregulation of glucose metabolism promotes an inflammatory phenotype of macrophages characterized by an oxidative stress-mediated increase in pro-inflammatory mediators [66].
Besides hyperglycemia, dyslipidemia is also a common feature of obesity and T2D. Therefore, integrative strategies that aim to improve the inflammatory and the metabolic profile characterizing these diseases are of paramount importance at the preventive level. One of these strategies includes physical exercise.

Exercise as an adjuvant: A COVID-19-centred perspective
Robert N. Butler once said: "if exercise could be packed into a pill, it would be the single most widely prescribed, and beneficial, medicine in the nation." [80]. Exercise is the only intervention that has the potential to confer wide spread preventive advantages, ranging from immuno-metabolic to mental health, against the deleterious effects of SARS-COV-2 outbreak. Since we cannot predict when the vaccine is going to be ready, when this outbreak will end, and if there will be new waves before discovering the vaccine, we need a strong shield -stronger than ever. Therefore we focus this section to discuss how exercise boosts our immune shield (see Figure2.), and how even if this shield is troubled, like in chronic diseases, exercise could restore functionality and confer some protection against COVID-19.
As highlighted earlier, obesity and diabetes status are major risk factors for contracting the severe form of COVID-19. Common to these conditions is a state of low grade inflammation and immune depression [31,33,34,[81][82][83][84], which is believed to contribute to the amplified immune response characterized by an overproduction of pro-inflammatory cytokines, namely the cytokine storm, typical of severe . Interestingly exercise by its anti-inflammatory effects may confer some protection by restoring the balance between pro and anti-inflammatory immune mediators.
A single bout of exercise is accompanied by a transient increase in . The rise of IL-6 is known to stimulate lipolysis which promotes fatty acid utilization as a fuel source binding IL-1 receptor [92]. The balance between IL-1/IL1ra is very important in health, and the disruption of this balance may lead to a broad range of diseases including insulin resistance [92][93][94]. This seems also to be valid in individuals with obesity, since acute moderate and high intensity interval exercises (HIIE) were shown to transiently increase IL-6 concentrations [95]. However, Dorneles, Haddad [96] showed that IL-6, IL-10 were only increased after HIIE. The relatively short duration (10 min) of the moderate intensity and the intermittent character of the exercise in this study could explain these discrepancies. The rise in catecholamines and cortisol, and their interference with acute exercise intensity could paly a role in theses anti-inflammatory effects [97,98]. Besides cytokines, exercise is also a potent inhibitor of TLRs, in health and T2D [99,100] Paradoxically, these anti-inflammatory effects, depending on exercise intensity and duration, may promote immunocompetence or immunodepression [101,102]. Acute moderate to vigorous intensity exercise of less than 60 min enhances immunocompetence and immunosurveillance because the rise in anti-inflammatory mediators is paralleled by an increased mobilization and activation of cytotoxic T cells, NK cells and neutrophils [103,104]. However, prolonged intense exercise -via the over-expression of anti-inflammatory cytokines -promotes a state of immunodepression [102,105]. These observations reflect that optimal immune function requires a balance in immune cells homeostasis, and/or in pro-and anti-inflammatory immune mediators. For instance, IL-10 is a potent modulator of Th1 and Tc1 T-cells, NK cells and macrophages activity, in part by moderating pro-inflammatory cytokines expression, which prevents excessive inflammation and tissue damage [90,106].
Conversely, over-abundant IL-10 impairs the inflammatory response and leads to pathogen persistence [107,108].
In trained athletes, Handzlik, Shaw [109] showed that high load endurance training induces heightened IL-10 expression upon ex-vivo antigen stimulation compared to sprint trained and sedentary counterparts. However, high training loads concern more elite athletes, and does not concern the general and the diseased populations, for which guidelines recommend 150 min/wk of moderate-intensity activity or 75 min/wk of vigorous-intensity activity [110,111], and even with such a small volume the majority of the population still not engage in regular exercise [112]. Moreover some researchers posited that the idea of intense exercise-mediated immunodepression is flawed, and that all the manifestations of immune depression accompanying intense exercise in athletes may in fact reflect an enhanced immune surveillance [113].
The balance between pro-inflammatory and anti-inflammatory immune cells subpopulations, and pro-inflammatory and anti-inflammatory immune mediators is critical for the immuno-metabolic health [114]. Any disruption in this balance increases susceptibility to diseases [115,116] . In the context of COVID-19, the severity of this disease is accompanied by comorbid states in which this balance is disrupted towards an inflammatory state. Exercise presents the most effective strategy that restores the anti-inflammatory component of this balance without compromising -if not optimally enhancing -the inflammatory response [101]. The anti-inflammatory component plays an important role during infection as it controls the inflammatory process through anti-inflammatory cytokines [90,102]. This prevents excess inflammation, and in the context of COVID-19 may prevent the cytokines storm. Of course these effects are intensity and duration dependent, but as highlighted above, unlike elite athletes, the general population does not regularly engage in intense prolonged exercise. Many reviews conclusively agreed that moderate to vigorous exercise of less than 60 min increases anti-pathogen activity and the mobilization of macrophages, NK cells, cytotoxic T cells, while in the same time, increases anti-inflammatory cytokines production, an environment that promotes metabolic health as well as optimal immune readiness [96,101,102].
Many reports showed that severe COVID-19 patients display reduced lymphocyte counts, particularly CD4+ and CD8+ T cells and increased cytokine levels 117,118]. CD4+ CD8+ T cells are very responsive to exercise in part because they carry more β2-adrenergic receptors [119,120], and display a dose dependent mobilization with exercise intensity [121,122]. Upon pathogen infection, the innate component of the immune system drives CD4+ and CD8+ T-cell polarization into two main subsets depending on their cytokines profiles: Type 1 T-cells (Th1,Tc1); exhibiting a proinflammatory cytokines profile (IFN-γ, IL-2), and are important in promoting intracellular pathogen defense and type 2 T-cells (Th2, Tc2), exhibiting an anti-inflammatory cytokine profile (IL-4, IL-10), and are important in mediating humoral immune response [123,124].
Th1 and Th2 for type 1and type 2 helper T cells are CD4+ polarized T-cells that play a more indirect role by recruiting more immune cells to the site of infection. Tc1 and Tc2, for type 1 and type 2 cytoxic T cells are CD8+ polarized T-cells that play a direct role in clearing intracellular pathogens [124,125]. Interestingly, Exercise is also known to enhance the functional capacity of these mature T cells in an intensity dependent manner [126]. That is, exercise influences the cytokines production by these cells; moderate intensity exercise increases type I cytokines production, which enhances the inflammatory response [127], while high intensity prolonged exercise decreases type 1 cytokines production, without affecting type 2 cytokines, which create an imbalance that may impair cellular defense [127,128].
Along with these acute exercise effects, chronic exercise training was reported to counteract T1 and T2 age-mediated cytokines reductions and lower the number of senescent T cells [101,129,130]. These changes in immune cells mobilization and function in response to exercise, both acute and chronic, have led many researchers to use exercise as a strategy to improve vaccine responsiveness [131]. Briefly, both acute and chronic moderate exercise were showed to improve vaccine responsiveness and to extend vaccine seroprotection, particularly in individuals vulnerable to immune dysfunction [131,132]. Moreover, in animal models studies of influenza infection, chronic exercise reduced symptoms, viral load and levels of inflammatory cytokines and chemokines [133]. Similarly another study showed that moderate exercise, early after influenza infection, reduced total cellular infiltration and IFN-γ gene expression in lungs, and shifted pro-inflammatory Th1 towards anti-inflammatory Th2 cells [134]. In line with these preclinical studies, epidemiological studies linked low to moderate exercise with reduced influenza mortality [135]. However this needs to be confirmed in clinical settings.
Based on these observations we speculate that exercise may hold substantial preventive effects against COVID-19 immunopathology. For specific physical activity recommendations during this period, readers are directed towards some recent articles [136,137] 5. Breaking up sedentary behavior: Get up from the couch and enjoy some movement As indicated above increased sedentary time constitutes a major risk factor for many chronic diseases, and could have been increased by shelter in place during this outbreak. and light intensity walking improved 24-h blood glucose profiles and insulin sensitivity to a greater extent than structured exercise does [140]. In subjects with obesity, Climie, Grace [141] showed that interruption of a 3,5-h TV watching with 3-min light intensity body weight resistance activity every 20 minutes attenuate glycemic excursions during TV watching after a high energy meal. In overweight sedentary women more frequent breaks of sedentary time resulted in improved postprandial insulin profiles compared to less frequent breaks matched for time and energy expenditure [142]. Even interrupting sitting with standing breaks was reported to significantly reduce blood glucose excursions compared to uninterrupted sitting [143]. A recent systematic review with meta-analysis concluded that breaking up sitting with moderate physical activity reduced postprandial blood glucose and insulin [144], however, smaller effects on triglycerides were observed. In addition, the reduction in blood glucose was more pronounced in subjects with higher BMI. When energy expenditure was matched, more frequent breaks of sedentary time were more consistent in reducing blood glucose levels.
Taken together, these studies suggest that interrupting prolonged sitting time with short bouts 75.