COVID-19 and obesity: fighting two pandemics with intermittent fasting
Authors: Kafi N. Ealey, Joy Phillips, Hoon-Ki Sung
Journal: Trends in Endocrinology and Metabolism (2021)

Obesity is a strong risk factor for severe illness and mortality from coronavirus disease 2019 (COVID-19) infection. Mechanisms linking obesity with severe COVID-19 include diabetes-associated hyperglycemia, inflammation, weakened immune function, and metabolic dysfunction.Obese populations have a known history of poor response to vaccination and it is unknown whether this will also affect their vaccine-induced immunity to COVID-19. Therefore, it is important to implement dietary and lifestyle changes that potentially boost metabolic and immune health to mitigate the impacts of COVID-19.Intermittent fasting (IF) is associated with weight loss, improved glucose homeostasis, metabolic health restoration, and strengthened immune responses.Amid COVID-19 lockdowns, which are associated with more-sedentary lifestyles, the incorporation of IF may be a practical way to curb unhealthy eating habits, maximize healthy lifestyles, and improve mood and emotional well-being. 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. 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. The COVID-19 pandemic has resulted in a major health crisis with devastating social and economic consequences. Studies from multiple clinical cohorts have shown that obesity is associated with increased complications, disease severity, and mortality on SARS-CoV-2 infection [1.Gao M. et al.Associations between body-mass index and COVID-19 severity in 6.9 million people in England: a prospective, community-based, cohort study.Lancet Diabetes Endocrinol. 2021; 9: 350-359Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 2.Kang Z. et al.Obesity is a potential risk factor contributing to clinical manifestations of COVID-19.Int. J. Obes. (Lond.). 2020; 44: 2479-2485Crossref PubMed Scopus (7) Google Scholar, 3.Simonnet A. et al.High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation.Obesity (Silver Spring). 2020; 28: 1195-1199Crossref PubMed Scopus (719) Google Scholar]. A risk assessment analysis of over 900 000 COVID-19 hospitalizations across the USA found that almost two-thirds of these hospitalizations were attributable to cardiometabolic conditions; namely, obesity, diabetes mellitus (DM), hypertension, and heart failure, with obesity accounting for 30% of hospitalizations [4.O'Hearn M. et al.Coronavirus disease 2019 hospitalizations attributable to cardiometabolic conditions in the United States: a comparative risk assessment analysis.J. Am. Heart Assoc. 2021; 10e019259PubMed Google Scholar]. COVID-19 patients with elevated body mass index (BMI) were reported to have significantly increased need for invasive mechanical ventilation, a robust proxy for severity of disease [3.Simonnet A. et al.High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation.Obesity (Silver Spring). 2020; 28: 1195-1199Crossref PubMed Scopus (719) Google Scholar], were more likely to develop severe pneumonia, exhibited more severe lung pathological changes and injury, and had increased risk of mortality compared with non-obese patients (BMI <25 kg/m2), independent of age, sex, diabetes, and hypertension [1.Gao M. et al.Associations between body-mass index and COVID-19 severity in 6.9 million people in England: a prospective, community-based, cohort study.Lancet Diabetes Endocrinol. 2021; 9: 350-359Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,2.Kang Z. et al.Obesity is a potential risk factor contributing to clinical manifestations of COVID-19.Int. J. Obes. (Lond.). 2020; 44: 2479-2485Crossref PubMed Scopus (7) Google Scholar,5.Hendren N.S. et al.Association of body mass index and age with morbidity and mortality in patients hospitalized with COVID-19: results from the American Heart Association COVID-19 Cardiovascular Disease Registry.Circulation. 2021; 143: 135-144Crossref PubMed Scopus (0) Google Scholar,6.Guerson-Gil A. et al.Sex-specific impact of severe obesity in the outcomes of hospitalized patients with COVID-19: a large retrospective study from the Bronx, New York.Eur. J. Clin. Microbiol. Infect. Dis. 2021; (Published online May 6, 2021. https://doi.org/10.1007/s10096-021-04260-z)Crossref PubMed Scopus (1) Google Scholar]. Unlike the rapid spread of COVID-19, the obesity pandemic has been slowly gaining momentum for decades. The global prevalence of obesity tripled between 1975 and 2016, and according to the World Health Organization over 650 million adults aged 18 years and over worldwide were obese in 2016 (https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight). Excess adipose tissue is a major source of proinflammatory factors that contribute to chronic systemic inflammation and a host of metabolic disturbances including type 2 DM (T2DM) [7.Alarcon P.C. et al.Adipocyte inflammation and pathogenesis of viral pneumonias: an overlooked contribution.Mucosal Immunol. 2021; (Published online May 6, 2021. https://doi.org/10.1038/s41385-021-00404-8)Crossref PubMed Scopus (0) Google Scholar]. Infection with SARS-CoV-2 elicits a wide spectrum of clinical responses (Box 1). Severe complications of COVID-19 infection and cytokine storm are more pronounced in individuals with elevated BMI and diabetes [2.Kang Z. et al.Obesity is a potential risk factor contributing to clinical manifestations of COVID-19.Int. J. Obes. (Lond.). 2020; 44: 2479-2485Crossref PubMed Scopus (7) Google Scholar,8.Codo A.C. et al.Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis.Cell Metab. 2020; 32: 437-446.e435Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar], suggesting that obesity-associated inflammation and metabolic dysfunction exacerbate the severity of illness, thus culminating in the dangerous intersection of two global pandemics.Box 1Clinical characteristics of SARS-CoV-2 infectionInfection with SARS-CoV-2 elicits a wide spectrum of clinical responses, ranging from asymptomatic infection to severe multisystem failure and respiratory distress. During the initial phase of infection, the entry of SARS-CoV-2 into the host cells activates innate immune signaling cascades, leading to increased secretion of proinflammatory cytokines, followed by functional adaptive immune responses that are critical for recovery and long-term immunity [93.Garcia L.F. Immune response, inflammation, and the clinical spectrum of COVID-19.Front. Immunol. 2020; 11: 1441Crossref PubMed Scopus (125) Google Scholar]. Approximately 1 week after the onset of COVID-19 symptoms, SARS-CoV-2-specific B and T cell responses can be detected in the blood [94.Suthar M.S. et al.Rapid generation of neutralizing antibody responses in COVID-19 patients.Cell Rep. Med. 2020; 1100040Abstract Full Text Full Text PDF PubMed Google Scholar]. These initial immune responses play a vital role in viral clearance through antibody production, the direct killing of virus-infected cells, and the production of cytokines that aid in immune cell recruitment [93.Garcia L.F. Immune response, inflammation, and the clinical spectrum of COVID-19.Front. Immunol. 2020; 11: 1441Crossref PubMed Scopus (125) Google Scholar,94.Suthar M.S. et al.Rapid generation of neutralizing antibody responses in COVID-19 patients.Cell Rep. Med. 2020; 1100040Abstract Full Text Full Text PDF PubMed Google Scholar]. While the majority of COVID-19 cases exhibit mild to moderate symptoms and eventually recover, approximately 15% exhibit dysfunctional immune responses characterized by uncontrolled proinflammatory cytokine release [95.Tang Y. et al.Cytokine storm in COVID-19: the current evidence and treatment strategies.Front. Immunol. 2020; 11: 1708Crossref PubMed Scopus (178) Google Scholar,96.Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention.JAMA. 2020; 323: 1239-1242Crossref PubMed Scopus (6539) Google Scholar]. This state of hyperinflammation, termed a cytokine storm, is thought to be the main driver of tissue injury, resulting in acute respiratory distress syndrome (ARDS), multiorgan failure, and ultimately death [32.Chen G. et al.Clinical and immunological features of severe and moderate coronavirus disease 2019.J. Clin. Invest. 2020; 130: 2620-2629Crossref PubMed Scopus (1591) Google Scholar]. Thus, compared with individuals who experience a normal recovery, patients with severe COVID-19 infection exhibit markedly increased serum levels of numerous proinflammatory cytokines [e.g., IL-6, IL-1β, IL-2, IL-8, IL-17, granulocyte colony-stimulating factor (G-CSF), granulocyte–macrophage CSF (GM-CSF), leptin, TNF-α] accompanied by immune cell impairment (e.g., higher percentages of pathogenic inflammatory monocytes, which propagate cytokine storms) [8.Codo A.C. et al.Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis.Cell Metab. 2020; 32: 437-446.e435Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar,32.Chen G. et al.Clinical and immunological features of severe and moderate coronavirus disease 2019.J. Clin. Invest. 2020; 130: 2620-2629Crossref PubMed Scopus (1591) Google Scholar,97.Zhang D. et al.Frontline science: COVID-19 infection induces readily detectable morphologic and inflammation-related phenotypic changes in peripheral blood monocytes.J. Leukoc. Biol. 2021; 109: 13-22Crossref PubMed Scopus (33) Google Scholar]. Decreased lymphocyte counts and abnormal lymphocyte functionality, including T cell exhaustion, have also been associated with increased COVID-19 severity [32.Chen G. et al.Clinical and immunological features of severe and moderate coronavirus disease 2019.J. Clin. Invest. 2020; 130: 2620-2629Crossref PubMed Scopus (1591) Google Scholar,93.Garcia L.F. Immune response, inflammation, and the clinical spectrum of COVID-19.Front. Immunol. 2020; 11: 1441Crossref PubMed Scopus (125) Google Scholar]. Infection with SARS-CoV-2 elicits a wide spectrum of clinical responses, ranging from asymptomatic infection to severe multisystem failure and respiratory distress. During the initial phase of infection, the entry of SARS-CoV-2 into the host cells activates innate immune signaling cascades, leading to increased secretion of proinflammatory cytokines, followed by functional adaptive immune responses that are critical for recovery and long-term immunity [93.Garcia L.F. Immune response, inflammation, and the clinical spectrum of COVID-19.Front. Immunol. 2020; 11: 1441Crossref PubMed Scopus (125) Google Scholar]. Approximately 1 week after the onset of COVID-19 symptoms, SARS-CoV-2-specific B and T cell responses can be detected in the blood [94.Suthar M.S. et al.Rapid generation of neutralizing antibody responses in COVID-19 patients.Cell Rep. Med. 2020; 1100040Abstract Full Text Full Text PDF PubMed Google Scholar]. These initial immune responses play a vital role in viral clearance through antibody production, the direct killing of virus-infected cells, and the production of cytokines that aid in immune cell recruitment [93.Garcia L.F. Immune response, inflammation, and the clinical spectrum of COVID-19.Front. Immunol. 2020; 11: 1441Crossref PubMed Scopus (125) Google Scholar,94.Suthar M.S. et al.Rapid generation of neutralizing antibody responses in COVID-19 patients.Cell Rep. Med. 2020; 1100040Abstract Full Text Full Text PDF PubMed Google Scholar]. While the majority of COVID-19 cases exhibit mild to moderate symptoms and eventually recover, approximately 15% exhibit dysfunctional immune responses characterized by uncontrolled proinflammatory cytokine release [95.Tang Y. et al.Cytokine storm in COVID-19: the current evidence and treatment strategies.Front. Immunol. 2020; 11: 1708Crossref PubMed Scopus (178) Google Scholar,96.Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention.JAMA. 2020; 323: 1239-1242Crossref PubMed Scopus (6539) Google Scholar]. This state of hyperinflammation, termed a cytokine storm, is thought to be the main driver of tissue injury, resulting in acute respiratory distress syndrome (ARDS), multiorgan failure, and ultimately death [32.Chen G. et al.Clinical and immunological features of severe and moderate coronavirus disease 2019.J. Clin. Invest. 2020; 130: 2620-2629Crossref PubMed Scopus (1591) Google Scholar]. Thus, compared with individuals who experience a normal recovery, patients with severe COVID-19 infection exhibit markedly increased serum levels of numerous proinflammatory cytokines [e.g., IL-6, IL-1β, IL-2, IL-8, IL-17, granulocyte colony-stimulating factor (G-CSF), granulocyte–macrophage CSF (GM-CSF), leptin, TNF-α] accompanied by immune cell impairment (e.g., higher percentages of pathogenic inflammatory monocytes, which propagate cytokine storms) [8.Codo A.C. et al.Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis.Cell Metab. 2020; 32: 437-446.e435Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar,32.Chen G. et al.Clinical and immunological features of severe and moderate coronavirus disease 2019.J. Clin. Invest. 2020; 130: 2620-2629Crossref PubMed Scopus (1591) Google Scholar,97.Zhang D. et al.Frontline science: COVID-19 infection induces readily detectable morphologic and inflammation-related phenotypic changes in peripheral blood monocytes.J. Leukoc. Biol. 2021; 109: 13-22Crossref PubMed Scopus (33) Google Scholar]. Decreased lymphocyte counts and abnormal lymphocyte functionality, including T cell exhaustion, have also been associated with increased COVID-19 severity [32.Chen G. et al.Clinical and immunological features of severe and moderate coronavirus disease 2019.J. Clin. Invest. 2020; 130: 2620-2629Crossref PubMed Scopus (1591) Google Scholar,93.Garcia L.F. Immune response, inflammation, and the clinical spectrum of COVID-19.Front. Immunol. 2020; 11: 1441Crossref PubMed Scopus (125) Google Scholar]. Currently, a number of COVID-19 vaccine candidates have undergone regulatory approval and are being used for vaccination. However, there remain barriers to achieving herd immunity, which is estimated to require that 60–70% of the population achieve immunity [9.Aschwanden C. Five reasons why COVID herd immunity is probably impossible.Nature. 2021; 591: 520-522Crossref PubMed Scopus (14) Google Scholar]. Factors such as vaccine hesitancy, manufacturing delays, distribution disparities, and the emergence of new, more transmissible SARS-CoV-2 variants that may be resistant to vaccines increase the potential for continued outbreaks [9.Aschwanden C. Five reasons why COVID herd immunity is probably impossible.Nature. 2021; 591: 520-522Crossref PubMed Scopus (14) Google Scholar]. Furthermore, obese populations have a known history of poor response to vaccination [10.Neidich S.D. et al.Increased risk of influenza among vaccinated adults who are obese.Int. J. Obes. 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Therefore, now more than ever, the world could benefit from the implementation of lifestyle changes that boost metabolic and immune health to mitigate the impacts of COVID-19. In this review, we present an overview of the relationship between obesity, adiposity, DM, and COVID-19 severity. We also propose a lifestyle regimen that incorporates IF (Box 2) as a promising strategy to improve metabolic health and immune function, potentially reducing the risk of severe illness from COVID-19. Finally, we offer our perspectives on some of the unique benefits and challenges of adopting IF during a global pandemic.Box 2Managing obesity through diet and exerciseRestriction of energy intake has beneficial effects on human health, including extended longevity, disease protection, and delayed aging [74.Longo V.D. Mattson M.P. Fasting: molecular mechanisms and clinical applications.Cell Metab. 2014; 19: 181-192Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar,98.Golbidi S. et al.Health benefits of fasting and caloric restriction.Curr. Diab. Rep. 2017; 17: 123Crossref PubMed Scopus (2) Google Scholar]. To address the difficulty of adhering to conventional, calorically restrictive weight-loss regimes, IF has gained popularity as an effective and practical alternative. Recently, IF has been shown to be an effective intervention for body weight regulation and glycemic control in many preclinical and clinical studies [59.Gabel K. et al.Effects of 8-hour time restricted feeding on body weight and metabolic disease risk factors in obese adults: a pilot study.Nutr. Healthy Aging. 2018; 4: 345-353Crossref PubMed Scopus (126) Google Scholar, 60.Kesztyus D. et al.Adherence to time-restricted feeding and impact on abdominal obesity in primary care patients: results of a pilot study in a pre-post design.Nutrients. 2019; 11: 2854Crossref Scopus (24) Google Scholar, 61.Cienfuegos S. et al.Effects of 4- and 6-h time-restricted feeding on weight and cardiometabolic health: a randomized controlled trial in adults with obesity.Cell Metab. 2020; 32: 366-378.e363Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,64.Kim Y.H. et al.Thermogenesis-independent metabolic benefits conferred by isocaloric intermittent fasting in ob/ob mice.Sci. Rep. 2019; 9: 2479Crossref PubMed Scopus (11) Google Scholar,65.Kim K.H. et al.Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage.Cell Res. 2017; 27: 1309-1326Crossref PubMed Scopus (61) Google Scholar]. Unlike CR, which is defined as a chronic 20–40% reduction of total caloric intake without any changes in meal frequency or timing [74.Longo V.D. Mattson M.P. Fasting: molecular mechanisms and clinical applications.Cell Metab. 2014; 19: 181-192Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar], IF involves recurring periods of fasting, alternating with AL food consumption [56.Lee J.H. et al.Intermittent fasting: physiological implications on outcomes in mice and men.Physiology (Bethesda). 2020; 35: 185-195PubMed Google Scholar]. Subtypes of IF are described in Figure I.Regular exercise of moderate to high intensity has been shown to reduce body weight and fat mass; however, evidence suggests that exercise alone generally leads to modest or clinically insignificant weight loss [99.Bellicha A. et al.Effect of exercise training on weight loss, body composition changes, and weight maintenance in adults with overweight or obesity: an overview of 12 systematic reviews and 149 studies.Obes. Rev. 2021; (Published online May 6, 2021. https://doi.org/10.1111/obr.13256)Crossref Scopus (2) Google Scholar]. One trial assessed the effects of combining IF with endurance exercise on 3 days per week for 12 weeks in obese adults [100.Bhutani S. et al.Alternate day fasting and endurance exercise combine to reduce body weight and favorably alter plasma lipids in obese humans.Obesity (Silver Spring). 2013; 21: 1370-1379Crossref PubMed Scopus (121) Google Scholar]. While body weight and BMI were reduced in both groups, the combination of both interventions resulted in a superior reduction in these parameters [100.Bhutani S. et al.Alternate day fasting and endurance exercise combine to reduce body weight and favorably alter plasma lipids in obese humans.Obesity (Silver Spring). 2013; 21: 1370-1379Crossref PubMed Scopus (121) Google Scholar]. Interestingly, fat mass significantly decreased in the IF and combination group but not the exercise group, potentially highlighting the limitations of exercise alone as an antiobesity approach [100.Bhutani S. et al.Alternate day fasting and endurance exercise combine to reduce body weight and favorably alter plasma lipids in obese humans.Obesity (Silver Spring). 2013; 21: 1370-1379Crossref PubMed Scopus (121) Google Scholar]. By contrast, one meta-analysis found that combining IF with resistance-training exercise had either small or inconsistent effects on decreasing body and fat mass compared with resistance training alone [101.Ashtary-Larky D. et al.Effects of intermittent fasting combined with resistance training on body composition: a systematic review and meta-analysis.Physiol. Behav. 2021; 237113453Crossref PubMed Scopus (0) Google Scholar], indicating a need for further studies to validate the advantages of combining exercise with IF.As recent evidence suggests that physical activity is protective against severe COVID-19 outcomes [102.Sallis R. et al.Physical inactivity is associated with a higher risk for severe COVID-19 outcomes: a study in 48 440 adult patients.Br. J. Sports Med. 2021; (Published online April 13, 2021. https://doi.org/10.1136/bjsports-2021-104080)Crossref Scopus (14) Google Scholar], a lifestyle that incorporates both physical activity and dietary intervention is likely to be an ideal approach to mitigating the impacts of COVID-19. However, during the COVID-19 pandemic, evidence suggests that social distancing has increased barriers to participation in physical activity [83.Stockwell S. et al.Changes in physical activity and sedentary behaviours from before to during the COVID-19 pandemic lockdown: a systematic review.BMJ Open Sport Exerc. Med. 2021; 7e000960Crossref PubMed Scopus (29) Google Scholar]. One benefit of IF is that it is a zero-cost and -time approach to managing weight, whereas exercise generally requires time, resources, and access to facilities – barriers associated with inactivity [103.Herazo-Beltran Y. et al.Predictors of perceived barriers to physical activity in the general adult population: a cross-sectional study.Braz. J. Phys. Ther. 2017; 21: 44-50Crossref PubMed Scopus (23) Google Scholar]. Thus, while exercise and IF are both attractive options for managing weight, IF may be a more pragmatic approach for some, particularly during the global pandemic. See Figure I for a description and comparison of weight-loss approaches. Restriction of energy intake has beneficial effects on human health, including extended longevity, disease protection, and delayed aging [74.Longo V.D. Mattson M.P. Fasting: molecular mechanisms and clinical applications.Cell Metab. 2014; 19: 181-192Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar,98.Golbidi S. et al.Health benefits of fasting and caloric restriction.Curr. Diab. Rep. 2017; 17: 123Crossref PubMed Scopus (2) Google Scholar]. To address the difficulty of adhering to conventional, calorically restrictive weight-loss regimes, IF has gained popularity as an effective and practical alternative. Recently, IF has been shown to be an effective intervention for body weight regulation and glycemic control in many preclinical and clinical studies [59.Gabel K. et al.Effects of 8-hour time restricted feeding on body weight and metabolic disease risk factors in obese adults: a pilot study.Nutr. Healthy Aging. 2018; 4: 345-353Crossref PubMed Scopus (126) Google Scholar, 60.Kesztyus D. et al.Adherence to time-restricted feeding and impact on abdominal obesity in primary care patients: results of a pilot study in a pre-post design.Nutrients. 2019; 11: 2854Crossref Scopus (24) Google Scholar, 61.Cienfuegos S. et al.Effects of 4- and 6-h time-restricted feeding on weight and cardiometabolic health: a randomized controlled trial in adults with obesity.Cell Metab. 2020; 32: 366-378.e363Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,64.Kim Y.H. et al.Thermogenesis-independent metabolic benefits conferred by isocaloric intermittent fasting in ob/ob mice.Sci. Rep. 2019; 9: 2479Crossref PubMed Scopus (11) Google Scholar,65.Kim K.H. et al.Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage.Cell Res. 2017; 27: 1309-1326Crossref PubMed Scopus (61) Google Scholar]. Unlike CR, which is defined as a chronic 20–40% reduction of total caloric intake without any changes in meal frequency or timing [74.Longo V.D. Mattson M.P. Fasting: molecular mechanisms and clinical applications.Cell Metab. 2014; 19: 181-192Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar], IF involves recurring periods of fasting, alternating with AL food consumption [56.Lee J.H. et al.Intermittent fasting: physiological implications on outcomes in mice and men.Physiology (Bethesda). 2020; 35: 185-195PubMed Google Scholar]. Subtypes of IF are described in Figure I. Regular exercise of moderate to high intensity has been shown to reduce body weight and fat mass; however, evidence suggests that exercise alone generally leads to modest or clinically insignificant weight loss [99.Bellicha A. et al.Effect of exercise training on weight loss, body composition changes, and weight maintenance in adults with overweight or obesity: an overview of 12 systematic reviews and 149 studies.Obes. Rev. 2021; (Published online May 6, 2021. https://doi.org/10.1111/obr.13256)Crossref Scopus (2) Google Scholar]. One trial assessed the effects of combining IF with endurance exercise on 3 days per week for 12 weeks in obese adults [100.Bhutani S. et al.Alternate day fasting and endurance exercise combine to reduce body weight and favorably alter plasma lipids in obese humans.Obesity (Silver Spring). 2013; 21: 1370-1379Crossref PubMed Scopus (121) Google Scholar]. While body weight and BMI were reduced in both groups, the combination of both interventions resulted in a superior reduction in these parameters [100.Bhutani S. et al.Alternate day fasting and endurance exercise combine to reduce body weight and favorably alter plasma lipids in obese humans.Obesity (Silver Spring). 2013; 21: 1370-1379Crossref PubMed Scopus (121) Google Scholar]. Interestingly, fat mass significantly decreased in the IF and combination group but not the exercise group, potentially highlighting the limitations of exercise alone as an antiobesity approach [100.Bhutani S. et al.Alternate day fasting and endurance exercise combine to reduce body weight and favorably alter plasma lipids in obese humans.Obesity (Silver Spring). 2013; 21: 1370-1379Crossref PubMed Scopus (121) Google Scholar]. By contrast, one met