Obesity, the most common comorbidity in SARS-CoV-2: is leptin the link?

Candida J Rebello, John P Kirwan, Frank L Greenway, Candida J Rebello, John P Kirwan, Frank L Greenway

Abstract

Overweight and obesity are major risk factors for diabetes, cardiovascular disease, and lung disease. These diseases are the most commonly reported health conditions that predispose individuals with SARS-CoV-2 infection to require hospitalization including intensive care unit admissions. The innate immune response is the host's first line of defense against a human coronavirus infection. However, most coronaviruses are armed with one strategy or another to overcome host antiviral defense, and the pathogenicity of the virus is related to its capacity to suppress host immunity. The multifaceted nature of obesity including its effects on immunity can fundamentally alter the pathogenesis of acute respiratory distress syndrome and pneumonia, which are the major causes of death due to SARS-CoV-2 infection. Elevated circulating leptin concentrations are a hallmark of obesity, which is associated with a leptin-resistant state. Leptin is secreted by adipocytes in proportion to body fat and regulates appetite and metabolism through signaling in the hypothalamus. However, leptin also signals through the Jak/STAT and Akt pathways, among others, to modulate T cell number and function. Thus, leptin connects metabolism with the immune response. Therefore, it seems appropriate that its dysregulation would have serious consequences during an infection. We propose that leptin may be the link between obesity and its high prevalence as a comorbidity of the SARS-CoV-2 infection. In this article, we present a synthesis of the mechanisms underpinning susceptibility to respiratory viral infections and the contribution of the immunomodulatory effects of obesity to the outcome.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1. Schematic summary of the immune…
Fig. 1. Schematic summary of the immune system activation and response to a viral infection.
Virion particles are illustrated by open pentagons. The three distinct types of IFNs include: type I IFNs (IFN-α and IFN-β), type II IFNs (IFN-γ), and type III IFNs (IFN-λ), All IFN types bind to distinct receptors but activate similar signaling pathways and transcriptional responses. The type I, type II, and type III IFN receptors are heterodimers composed of IFNAR1 and IFNAR2 subunits, IFNGR1 and IFNGR2 subunits, and IFNLR1 and IL10Rβ subunits, respectively. Viral-encoded products antagonize the IFN-signaling pathways and the biochemical activity of IFN-induced cellular proteins to thwart host antiviral defense. In activated lymphocytes, lipid oxidation is downregulated and glycolysis increases in the presence of oxygen, together with glutamine oxidation in order to produce the biosynthetic precursors required for rapid cell growth and proliferation. Leptin signals via the Jak/STAT and Akt pathways among others to mediate immune cell number and function. Leptin dysregulation in obesity has detrimental effects during an infection. LepR: leptin receptor.

References

    1. WHO. Obesity and Overweight. 2018. . Accessed 5 April 2020.
    1. Prospective Studies C, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009;373:1083–96. doi: 10.1016/S0140-6736(09)60318-4.
    1. Masters RK, Powers DA, Link BG. Obesity and US mortality risk over the adult life course. Am J Epidemiol. 2013;177:431–42. doi: 10.1093/aje/kws325.
    1. Global BMIMC, Di Angelantonio E, Bhupathiraju Sh N, Wormser D, Gao P, Kaptoge S, et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016;388:776–86. doi: 10.1016/S0140-6736(16)30175-1.
    1. Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2009;121:21–33. doi: 10.3810/pgm.2009.11.2074.
    1. Omran AR. The epidemiologic transition: a theory of the epidemiology of population change. Milbank Mem Fund Q. 1971;49:509–38. doi: 10.2307/3349375.
    1. Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and management of obesity. N Engl J Med. 2017;376:1492. doi: 10.1056/NEJMra1514009.
    1. CDC. 2009 H1N1 Pandemic (H1N1pdm09 virus). 2020. . Accessed 10 April 2020.
    1. CDC. Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019—United States, February 12–March 28, 2020. 2020. . Accessed 10 April 2020.
    1. CDC. National Diabetes Statistics Report. 2020. . Accessed 6 April 2020.
    1. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation. 2020;141:e139–e596.
    1. American Lung Association. Estimated Prevalence and Incidence of Lung Disease. 2020. . Accessed 10 April 2020.
    1. Milner JJ, Beck MA. The impact of obesity on the immune response to infection. Proc Nutr Soc. 2012;71:298–306. doi: 10.1017/S0029665112000158.
    1. Huttunen R, Syrjanen J. Obesity and the outcome of infection. Lancet Infect Dis. 2010;10:442–3. doi: 10.1016/S1473-3099(10)70103-1.
    1. Louie JK, Acosta M, Samuel MC, Schechter R, Vugia DJ, Harriman K, et al. A novel risk factor for a novel virus: obesity and 2009 pandemic influenza A (H1N1) Clin Infect Dis. 2011;52:301–12. doi: 10.1093/cid/ciq152.
    1. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323:2052–2059.
    1. Sattar N, McInnes IB, McMurray JJV. Obesity a risk factor for severe COVID-19 infection: multiple potential mechanisms. Circulation. 2020;142:4–6. doi: 10.1161/CIRCULATIONAHA.120.047659.
    1. Simonnet A, Chetboun M, Poissy J, Raverdy V, Noulette J, Duhamel A, et al. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation. Obesity. 2020;28:1195–1199. doi: 10.1002/oby.22831.
    1. Barrasa H, Rello J, Tejada S, Martin A, Balziskueta G, Vinuesa C et al. SARS-Cov-2 in Spanish intensive care: early experience with 15-day survival in Vitoria. Anaesth Crit Care Pain Med. 2020. 10.1016/j.accpm.2020.04.001.
    1. Kass DA, Duggal P, Cingolani O. Obesity could shift severe COVID-19 disease to younger ages. Lancet. 2020;395:1544–5. doi: 10.1016/S0140-6736(20)31024-2.
    1. Peters U, Suratt BT, Bates JHT, Dixon AE. Beyond BMI: obesity and lung disease. Chest. 2018;153:702–9. doi: 10.1016/j.chest.2017.07.010.
    1. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–80.e8. doi: 10.1016/j.cell.2020.02.052.
    1. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020;5:562–9. doi: 10.1038/s41564-020-0688-y.
    1. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020;176:104742. doi: 10.1016/j.antiviral.2020.104742.
    1. Wong LY, Lui PY, Jin DY. A molecular arms race between host innate antiviral response and emerging human coronaviruses. Virol Sin. 2016;31:12–23. doi: 10.1007/s12250-015-3683-3.
    1. Lazear HM, Schoggins JW, Diamond MS. Shared and distinct functions of type I and type III interferons. Immunity. 2019;50:907–23. doi: 10.1016/j.immuni.2019.03.025.
    1. Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. Nat Rev Immunol. 2014;14:315–28. doi: 10.1038/nri3665.
    1. Broggi A, Granucci F, Zanoni I. Type III interferons: balancing tissue tolerance and resistance to pathogen invasion. J Exp Med. 2020;217:e20190295.
    1. Jewell NA, Cline T, Mertz SE, Smirnov SV, Flano E, Schindler C, et al. Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo. J Virol. 2010;84:11515–22. doi: 10.1128/JVI.01703-09.
    1. Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev. 2001;14:778–809. doi: 10.1128/CMR.14.4.778-809.2001.
    1. Fung SY, Yuen KS, Ye ZW, Chan CP, Jin DY. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect. 2020;9:558–70. doi: 10.1080/22221751.2020.1736644.
    1. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R, et al. Imbalanced Host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181:1036–45.e9. doi: 10.1016/j.cell.2020.04.026.
    1. He L, Ding Y, Zhang Q, Che X, He Y, Shen H, et al. Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. J Pathol. 2006;210:288–97. doi: 10.1002/path.2067.
    1. Ubags ND, Stapleton RD, Vernooy JH, Burg E, Bement J, Hayes CM et al. Hyperleptinemia is associated with impaired pulmonary host defense. JCI Insight. 2016;1:e82101.
    1. Fung TS, Liu DX. Human coronavirus: host-pathogen interaction. Annu Rev Microbiol. 2019;73:529–57. doi: 10.1146/annurev-micro-020518-115759.
    1. Mar KB, Rinkenberger NR, Boys IN, Eitson JL, McDougal MB, Richardson RB, et al. LY6E mediates an evolutionarily conserved enhancement of virus infection by targeting a late entry step. Nat Commun. 2018;9:3603. doi: 10.1038/s41467-018-06000-y.
    1. Zhao X, Guo F, Liu F, Cuconati A, Chang J, Block TM, et al. Interferon induction of IFITM proteins promotes infection by human coronavirus OC43. Proc Natl Acad Sci USA. 2014;111:6756–61. doi: 10.1073/pnas.1320856111.
    1. Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020;181:1016–35.e19. doi: 10.1016/j.cell.2020.04.035.
    1. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–6. doi: 10.1038/nature03712.
    1. Zou Z, Yan Y, Shu Y, Gao R, Sun Y, Li X, et al. Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun. 2014;5:3594. doi: 10.1038/ncomms4594.
    1. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11:875–9. doi: 10.1038/nm1267.
    1. Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe. 2016;19:181–93. doi: 10.1016/j.chom.2016.01.007.
    1. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39:529–39. doi: 10.1007/s00281-017-0629-x.
    1. Davidson S, Maini MK, Wack A. Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J Interferon Cytokine Res. 2015;35:252–64. doi: 10.1089/jir.2014.0227.
    1. Kordonowy LL, Burg E, Lenox CC, Gauthier LM, Petty JM, Antkowiak M, et al. Obesity is associated with neutrophil dysfunction and attenuation of murine acute lung injury. Am J Respir Cell Mol Biol. 2012;47:120–7. doi: 10.1165/rcmb.2011-0334OC.
    1. Mancuso P. Obesity and lung inflammation. J Appl Physiol. 2010;108:722–8. doi: 10.1152/japplphysiol.00781.2009.
    1. MacIver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. Annu Rev Immunol. 2013;31:259–83. doi: 10.1146/annurev-immunol-032712-095956.
    1. Martin-Romero C, Sanchez-Margalet V. Human leptin activates PI3K and MAPK pathways in human peripheral blood mononuclear cells: possible role of Sam68. Cell Immunol. 2001;212:83–91. doi: 10.1006/cimm.2001.1851.
    1. Sanchez-Margalet V, Martin-Romero C. Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway. Cell Immunol. 2001;211:30–6. doi: 10.1006/cimm.2001.1815.
    1. Matarese G, Moschos S, Mantzoros CS. Leptin in immunology. J Immunol. 2005;174:3137–42. doi: 10.4049/jimmunol.174.6.3137.
    1. Saucillo DC, Gerriets VA, Sheng J, Rathmell JC, Maciver NJ. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J Immunol. 2014;192:136–44. doi: 10.4049/jimmunol.1301158.
    1. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature. 1998;394:897–901. doi: 10.1038/29795.
    1. Chan JL, Matarese G, Shetty GK, Raciti P, Kelesidis I, Aufiero D, et al. Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans. Proc Natl Acad Sci USA. 2006;103:8481–6. doi: 10.1073/pnas.0505429103.
    1. Mansour E, Pereira FG, Araujo EP, Amaral ME, Morari J, Ferraroni NR, et al. Leptin inhibits apoptosis in thymus through a janus kinase-2-independent, insulin receptor substrate-1/phosphatidylinositol-3 kinase-dependent pathway. Endocrinology. 2006;147:5470–9. doi: 10.1210/en.2006-0223.
    1. Zhang AJ, To KK, Li C, Lau CC, Poon VK, Chan CC, et al. Leptin mediates the pathogenesis of severe 2009 pandemic influenza A(H1N1) infection associated with cytokine dysregulation in mice with diet-induced obesity. J Infect Dis. 2013;207:1270–80. doi: 10.1093/infdis/jit031.
    1. Teran-Cabanillas E, Montalvo-Corral M, Caire-Juvera G, Moya-Camarena SY, Hernandez J. Decreased interferon-alpha and interferon-beta production in obesity and expression of suppressor of cytokine signaling. Nutrition. 2013;29:207–12. doi: 10.1016/j.nut.2012.04.019.
    1. Besedovsky HO, del Rey A. Immune-neuro-endocrine interactions: facts and hypotheses. Endocr Rev. 1996;17:64–102. doi: 10.1210/edrv-17-1-64.
    1. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382:250–2. doi: 10.1038/382250a0.
    1. Matarese G, La Cava A, Sanna V, Lord GM, Lechler RI, Fontana S, et al. Balancing susceptibility to infection and autoimmunity: a role for leptin? Trends Immunol. 2002;23:182–7. doi: 10.1016/S1471-4906(02)02188-9.
    1. De Rosa V, Procaccini C, Cali G, Pirozzi G, Fontana S, Zappacosta S, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity. 2007;26:241–55. doi: 10.1016/j.immuni.2007.01.011.
    1. Procaccini C, De Rosa V, Galgani M, Abanni L, Cali G, Porcellini A, et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity. 2010;33:929–41. doi: 10.1016/j.immuni.2010.11.024.
    1. La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol. 2004;4:371–9. doi: 10.1038/nri1350.
    1. Liu AG, Smith SR, Fujioka K, Greenway FL. The effect of leptin, caffeine/ephedrine, and their combination upon visceral fat mass and weight loss. Obesity. 2013;21:1991–6. doi: 10.1002/oby.20416.
    1. Galgani JE, Greenway FL, Caglayan S, Wong ML, Licinio J, Ravussin E. Leptin replacement prevents weight loss-induced metabolic adaptation in congenital leptin-deficient patients. J Clin Endocrinol Metab. 2010;95:851–5. doi: 10.1210/jc.2009-1739.
    1. Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, et al. Leptin mediates the increase in blood pressure associated with obesity. Cell. 2014;159:1404–16. doi: 10.1016/j.cell.2014.10.058.
    1. Kelly KR, Williamson DL, Fealy CE, Kriz DA, Krishnan RK, Huang H, et al. Acute altitude-induced hypoxia suppresses plasma glucose and leptin in healthy humans. Metabolism. 2010;59:200–5. doi: 10.1016/j.metabol.2009.07.014.
    1. Barkoukis H, Marchetti CM, Nolan B, Sistrun SN, Krishnan RK, Kirwan JP. A high glycemic meal suppresses the postprandial leptin response in normal healthy adults. Ann Nutr Metab. 2007;51:512–8. doi: 10.1159/000112309.
    1. Friedman JM. Modern science versus the stigma of obesity. Nat Med. 2004;10:563–9. doi: 10.1038/nm0604-563.
    1. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995;1:1155–61. doi: 10.1038/nm1195-1155.
    1. Jain M, Budinger GR, Lo A, Urich D, Rivera SE, Ghosh AK, et al. Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-gamma. Am J Respir Crit Care Med. 2011;183:1490–8. doi: 10.1164/rccm.201009-1409OC.
    1. Frauwirth KA, Thompson CB. Regulation of T lymphocyte metabolism. J Immunol. 2004;172:4661–5. doi: 10.4049/jimmunol.172.8.4661.
    1. Fischer HJ, Sie C, Schumann E, Witte AK, Dressel R, van den Brandt J, et al. The insulin receptor plays a critical role in T cell function and adaptive immunity. J Immunol. 2017;198:1910–20. doi: 10.4049/jimmunol.1601011.
    1. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7. doi: 10.1038/nature05485.
    1. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW., Jr Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808. doi: 10.1172/JCI200319246.
    1. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15:914–20. doi: 10.1038/nm.1964.
    1. O’Brien JM, Jr., Welsh CH, Fish RH, Ancukiewicz M, Kramer AM, National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network. Excess body weight is not independently associated with outcome in mechanically ventilated patients with acute lung injury. Ann Intern Med. 2004;140:338–45. doi: 10.7326/0003-4819-140-5-200403020-00009.
    1. Anzueto A, Frutos-Vivar F, Esteban A, Bensalami N, Marks D, Raymondos K, et al. Influence of body mass index on outcome of the mechanically ventilated patients. Thorax. 2011;66:66–73. doi: 10.1136/thx.2010.145086.
    1. Jose RJ, Manuel A. Does COVID-19 disprove the obesity paradox in ARDS? Obesity. 2020;6:1007. doi: 10.1002/oby.22835.
    1. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–9. doi: 10.1172/JCI137244.
    1. Wang F, Nie J, Wang H, Zhao Q, Xiong Y, Deng L, et al. Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. J Infect Dis. 2020;221:1762–9. doi: 10.1093/infdis/jiaa150.
    1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–62. doi: 10.1016/S0140-6736(20)30566-3.
    1. Chen J, Lau YF, Lamirande EW, Paddock CD, Bartlett JH, Zaki SR, et al. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J Virol. 2010;84:1289–301. doi: 10.1128/JVI.01281-09.
    1. Liu PP, Blet A, Smyth D, Li H. The science underlying COVID-19: implications for the cardiovascular system. Circulation. 2020. 10.1161/CIRCULATIONAHA.120.047549.
    1. Green WD, Beck MA. Obesity impairs the adaptive immune response to influenza virus. Ann Am Thorac Soc. 2017;14(Supplement_5):S406–S409. doi: 10.1513/AnnalsATS.201706-447AW.
    1. Gattinoni L, Coppola S, Cressone M, Busana M, Rossi S, Chiumello D. Covid-19 does not lead to “typical” acute respiratory distress syndrome. Am J Respir Crit Care Med. 2020;201:1299–1300. doi: 10.1164/rccm.202003-0817LE.
    1. Dietz W, Santos-Burgoa C. Obesity and its implications for COVID-19 mortality. Obesity. 2020;28:1005. doi: 10.1002/oby.22818.
    1. Wilson KC, Chotirmall SH, Chunxue B, Rello J. Covid-19. Interim Guidance on Management Pending Empirical Evidence from an American Thoracic Society-Led International Task Force. 2020. . Accessed 20 April 2020.
    1. Sharp JT, Henry JP, Sweany SK, Meadows WR, Pietras RJ. The total work of breathing in normal and obese men. J Clin Invest. 1964;43:728–39. doi: 10.1172/JCI104957.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj