COVID-19 and obesity: fighting two pandemics with intermittent fasting
Journal: 2021/July - Trends in Endocrinology and Metabolism
Abstract:
Obesity is strongly and independently associated with an increased risk of severe illness and death from coronavirus disease 2019 (COVID-19). The pathophysiological changes that result from elevated body weight lead to metabolic dysfunction, chronic inflammation, impaired immunological responses, and multisystem disorders, which increase vulnerability to severe illness from COVID-19. While vaccination strategies are under way across the world, the second and third waves of the pandemic, along with the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains, continue to threaten the stability of medical systems worldwide. Furthermore, evidence from previous pandemics suggests that vaccines are less effective in obese individuals than in their healthy-weight counterparts over the long term. Therefore, a consideration of lifestyle changes that can boost metabolic health and immunity is critical to reduce the risk of complications and severe illness from viral infection. In this review, we discuss the potential mechanisms linking excess body weight with COVID-19 morbidity. We also present evidence that intermittent fasting (IF), a dietary program that has gained popularity in recent years, may be an effective strategy to improve metabolic health and immunity and thus reduce the impact of obesity on COVID-19 morbidity and mortality.
Keywords: COVID-19; diabetes; immune response; intermittent fasting; obesity.
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COVID-19 and obesity: fighting two pandemics with intermittent fasting

Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Correspondence:
These authors contributed equally to this work
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Obesity is strongly and independently associated with an increased risk of severe illness and death from coronavirus disease 2019 (COVID-19). The pathophysiological changes that result from elevated body weight lead to metabolic dysfunction, chronic inflammation, impaired immunological responses, and multisystem disorders, which increase vulnerability to severe illness from COVID-19. While vaccination strategies are under way across the world, the second and third waves of the pandemic, along with the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains, continue to threaten the stability of medical systems worldwide. Furthermore, evidence from previous pandemics suggests that vaccines are less effective in obese individuals than in their healthy-weight counterparts over the long term. Therefore, a consideration of lifestyle changes that can boost metabolic health and immunity is critical to reduce the risk of complications and severe illness from viral infection. In this review, we discuss the potential mechanisms linking excess body weight with COVID-19 morbidity. We also present evidence that intermittent fasting (IF), a dietary program that has gained popularity in recent years, may be an effective strategy to improve metabolic health and immunity and thus reduce the impact of obesity on COVID-19 morbidity and mortality.
Clinical characteristics of SARS-CoV-2 infection
Alt-text: Box 1
Managing obesity through diet and exercise
Comparing healthy lifestyle approaches.
Lifestyle interventions that support the management of obesity and promote metabolic health include caloric restriction (CR), alternate-day fasting (ADF), time-restricted feeding (TRF), and physical exercise. These interventions have all been shown to improve body composition and glucose homeostasis [56639899]. Unlike ADF and TRF [subtypes of intermittent fasting (IF)], exercise regimens require time and, often, financial resources to implement. Depending on the circumstances, this can be a burden associated with CR regimens as well. Moreover, energy intake is chronically restricted with CR, creating unique challenges for long-term adherence. A major benefit of ADF and TRF is that overall energy intake is not restricted, although this is often an unintended consequence of these regimens [59]. Meal timing is, however, restricted with IF, posing distinct adherence challenges. Figure created with BioRender.com. Abbreviation: BMI, body mass index.
Alt-text: Box 2
Hyperglycemia-mediated coronavirus disease 2019 (COVID-19) pathogenesis.
Hyperglycemia and poor glycemic control are independently associated with the severity of COVID-19 and increase the risk of mortality [17.18.19.2122]. The pathophysiological mechanisms for this association may be related to increased activation of glucose metabolic pathways. Increased hexosamine biosynthesis by viral infection contributes to cytokine storms through upregulation of interferon regulatory factor-5 (IRF5) [2324], a marker of metabolic inflammation that is elevated in adipose tissues of obese individuals [2526]. Hyperglycemia was associated with increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in monocytes from human obese diabetic patients, leading to sustained viral proliferation, induction of cytokine storm, and T cell dysfunction [8]. Furthermore, hyperglycemia may potentiate the glycosylation of the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) [2829]. Figure created with BioRender.com.
Abbreviations: ARDS, acute respiratory distress syndrome; HIF-1a, hypoxia-inducible factor-1α; ROS, reactive oxygen species.
Tissue ACE2 expression and relationship to COVID-19 pathogenesis
Alt-text: Box 3
Impact of obesity on metabolic and immune function.
The accumulation of excess fat is characterized by a phenotypic shift from an anti-inflammatory to a proinflammatory tissue microenvironment, including an increased ratio of proinflammatory (M1-like) to anti-inflammatory (M2-like) macrophages, enhanced polarization toward T helper 1 (Th1), Th17, and CD8 cytotoxic T cells, and reduced regulatory T cells [7]. These changes result in an increase in the baseline circulating levels of proinflammatory cytokines [e.g., interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), IL-1β, leptin] [733] and the frequency of monocytes. Increased proinflammatory cytokines may exacerbate the risk of virus-induced cytokine storms and drive tissue injury, resulting in acute respiratory distress syndrome (ARDS), multiorgan failure, and ultimately death [1297]. Attenuated immune cell activation and impaired memory T cell responses in obese populations result in poor outcomes from viral infection and reduce the efficacy of vaccines [10]. Obesity results in impaired gut physiology, including increased barrier permeability and microbiome dysbiosis [51]. As the gastrointestinal system (GI) is thought to be a target for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry, poor gut health may be a predisposing factor for the development of severe coronavirus disease 2019 (COVID-19). Figure created with BioRender.com. Abbreviation: T2DM, type 2 diabetes mellitus.
Intermittent fasting (IF) and glucose homeostasis.
Evidence from both preclinical and clinical studies indicates that various IF regimens improve glucose homeostasis and insulin sensitivity, even in the absence of weight loss or no change in overall energy expenditure [6365]. We propose that glycemic control by IF could contribute to lowering the risk of severe complications from coronavirus disease 2019 (COVID-19). Figure created with BioRender.com. Abbreviation: GLP-1, glucagon-like peptide 1.
Alt-text: Outstanding questions
Key figure. Intermittent fasting (IF) in the time of coronavirus disease 2019 (COVID-19).
While the number of vaccine candidates for COVID-19 continues to increase, many hurdles exist surrounding global distribution, access, and vaccine hesitancy [9]. Thus, the feasibility of tackling this global pandemic and achieving population herd immunity remains unclear. In addition to these challenges, second and third waves of infection have resulted in stay-at-home orders and imposed lockdowns for billions of individuals worldwide. The toll of widespread social isolation includes a shift to more sedentary lifestyles, drastic changes in eating and lifestyle habits, and increased stress culminating in declining physical and mental health [82848687]. We propose that the incorporation of healthy eating strategies, such as IF, that are reported to boost immune health, restore metabolic function, and improve glucose homeostasis is especially important during this time, particularly for obese individuals. IF strategies are particularly suited to the unique social climate of stay-at-home orders, as they do not require major alterations in diet composition but instead restrict eating to discrete time windows. Figure created with BioRender.com.

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