Plasma Leptin Is Increased in Intensive Care Patients with COVID-19—An Investigation Performed in the PronMed-Cohort

Larsson, Anders; Lipcsey, Miklós; Hultström, Michael; Frithiof, Robert; Eriksson, Mats

doi:10.3390/biomedicines10010004

Cited by 22 publications

(21 citation statements)

References 42 publications

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“…We and others have hypothesized that this chronic inflammatory state in individuals with obesity might exacerbate the immunopathology associated with SARS-CoV-2 infection in patients with obesity thereby rendering them susceptible to severe organ injury [ 11 , 12 ]. In line with this hypothesis, recent small studies from our group and others identified that plasma leptin was increased in COVID-19 patients admitted to the ICU [ 11 , 13 , 14 ]. Yet a decrease in Leptin in severe COVID-19 patients compared to mild and moderate COVID-19 was also found [ 15 ].…”

Section: Introductionsupporting

confidence: 63%

Circulating adipokine levels and COVID-19 severity in hospitalized patients

et al. 2022

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Background Obesity is a risk factor for adverse outcomes in COVID-19, potentially driven by chronic inflammatory state due to dysregulated secretion of adipokines and cytokines. We investigated the association between plasma adipokines and COVID-19 severity, systemic inflammation, clinical parameters, and outcome of COVID-19 patients. Methods In this multi-centre prospective cross-sectional study, we collected blood samples and clinical data from COVID-19 patients. The severity of COVID-19 was classified as mild (no hospital admission), severe (ward admission), and critical (ICU admission). ICU non-COVID-19 patients were also included and plasma from healthy age, sex, and BMI-matched individuals obtained from Lifelines. Multi-analyte profiling of plasma adipokines (Leptin, Adiponectin, Resistin, Visfatin) and inflammatory markers (IL-6, TNFα, IL-10) were determined using Luminex multiplex assays. Results Between March and December 2020, 260 SARS-CoV-2 infected individuals (age: 65 [56–74] BMI 27.0 [24.4–30.6]) were included: 30 mild, 159 severe, and 71 critical patients. Circulating leptin levels were reduced in critically ill patients with a high BMI yet this decrease was absent in patients that were administered dexamethasone. Visfatin levels were higher in critical COVID-19 patients compared to non-COVID-ICU, mild and severe patients (4.7 vs 3.4, 3.0, and 3.72 ng/mL respectively, p < 0.05). Lower Adiponectin levels, but higher Resistin levels were found in severe and critical patients, compared to those that did not require hospitalization (3.65, 2.7 vs 7.9 µg/mL, p < 0.001, and 18.2, 22.0 vs 11.0 ng/mL p < 0.001). Conclusion Circulating adipokine levels are associated with COVID-19 hospitalization, i.e., the need for oxygen support (general ward), or the need for mechanical ventilation and other organ support in the ICU, but not mortality.

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Section: Introductionsupporting

confidence: 63%

Circulating adipokine levels and COVID-19 severity in hospitalized patients

et al. 2022

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“…In the metaflammation of obesity, the inflamed adipose tissue is the driving force. The chronically slightly elevated proinflammatory cytokines (including leptin, which has been found to be elevated in COVID-19 patients [ 202 , 270 , 271 , 272 ]— Table 1 ) can cause SOCS1/3 induction [ 23 , 254 ], thus inhibiting the signaling of cytokines (such as interferons), leptin, and insulin [ 254 , 268 ]. “Resistance” arises, and that affects various organs, including parts of the immune system.…”

Section: Comprehensive Summary and Discussionmentioning

confidence: 99%

Obesity and Leptin Resistance in the Regulation of the Type I Interferon Early Response and the Increased Risk for Severe COVID-19

et al. 2022

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Obesity, and obesity-associated conditions such as hypertension, chronic kidney disease, type 2 diabetes, and cardiovascular disease, are important risk factors for severe Coronavirus disease-2019 (COVID-19). The common denominator is metaflammation, a portmanteau of metabolism and inflammation, which is characterized by chronically elevated levels of leptin and pro-inflammatory cytokines. These induce the “Suppressor Of Cytokine Signaling 1 and 3” (SOCS1/3), which deactivates the leptin receptor and also other SOCS1/3 sensitive cytokine receptors in immune cells, impairing the type I and III interferon early responses. By also upregulating SOCS1/3, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 adds a significant boost to this. The ensuing consequence is a delayed but over-reactive immune response, characterized by high-grade inflammation (e.g., cytokine storm), endothelial damage, and hypercoagulation, thus leading to severe COVID-19. Superimposing an acute disturbance, such as a SARS-CoV-2 infection, on metaflammation severely tests resilience. In the long run, metaflammation causes the “typical western” conditions associated with metabolic syndrome. Severe COVID-19 and other serious infectious diseases can be added to the list of its short-term consequences. Therefore, preventive measures should include not only vaccination and the well-established actions intended to avoid infection, but also dietary and lifestyle interventions aimed at improving body composition and preventing or reversing metaflammation.

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“…High levels of plasma leptin and adipokines are directly associated with the extent of obesity and have previously been shown to facilitate endothelial dysfunction (5,(20)(21)(22). Moreover, we and others reported before that plasma leptin levels are increased in critically ill COVID-19 patients (8,10,11). We therefore hypothesized that adipokines such as leptin may prime endothelial cells, thereby facilitating SARS-CoV-2 sensing and/or infection and driving the endothelial dysfunction which is characteristic of severe COVID-19.…”

Section: Leptin Does Not Facilitate Infection Nor Promote Activation ...mentioning

confidence: 87%

“…It is therefore hypothesized that this chronic inflammatory state might exacerbate the immune responses to SARS-CoV-2 infection in obese patients rendering them susceptible to severe disease (8,9). In line with this hypothesis, recent studies found plasma leptin to be increased in COVID-19 patients admitted to the intensive care (8,10,11).…”

Section: Introductionmentioning

confidence: 95%

Mediators of Obesity Do Not Influence SARS-CoV-2 Infection or Activation of Primary Human Lung Microvascular Endothelial Cells In Vitro

et al. 2022

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Clinical observations have shown that obesity is associated with the severe outcome of SARS-CoV-2 infection hallmarked by microvascular dysfunction in the lungs and other organs. Excess visceral fat and high systemic levels of adipose tissue (AT) derived mediators such as leptin and other adipokines have also been linked to endothelial dysfunction. Consequently, we hypothesized that AT-derived mediators may exacerbate microvascular dysfunction during of SARS-CoV-2 infection and tested this in a primary human lung microvascular endothelial (HLMVEC) cell model. Our results indicate that HLMVEC are not susceptible to SARS-CoV-2 infection since no expression of viral proteins and no newly produced virus was detected. In addition, exposure to the virus did not induce endothelial activation as evidenced by a lack of adhesion molecule, E-selectin, VCAM-1, ICAM-1, and inflammatory cytokine IL-6 induction. Incubation of endothelial cells with the pro-inflammatory AT-derived mediator, leptin, prior to virus inoculation, did not alter the expression of endothelial SARS-CoV-2 entry receptors and did not alter their susceptibility to infection. Furthermore, it did not induce inflammatory activation of endothelial cells. To verify if the lack of activated phenotype in the presence of adipokines was not leptin-specific, we exposed endothelial cells to plasma obtained from critically ill obese COVID-19 patients. Plasma exposure did not result in E-selectin, VCAM-1, ICAM-1, or IL-6 induction. Together our results strongly suggest that aberrant inflammatory endothelial responses are not mounted by direct SARS-CoV-2 infection of endothelial cells, even in the presence of leptin and other mediators of obesity. Instead, endothelial activation associated with COVID-19 is likely a result of inflammatory responses initiated by other cells. Further studies are required to investigate the mechanisms regulating endothelial behavior in COVID-19 and the mechanisms driving severe disease in obese individuals.

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Plasma Leptin Is Increased in Intensive Care Patients with COVID-19—An Investigation Performed in the PronMed-Cohort

Cited by 22 publications

References 42 publications

Circulating adipokine levels and COVID-19 severity in hospitalized patients

Circulating adipokine levels and COVID-19 severity in hospitalized patients

Obesity and Leptin Resistance in the Regulation of the Type I Interferon Early Response and the Increased Risk for Severe COVID-19

Mediators of Obesity Do Not Influence SARS-CoV-2 Infection or Activation of Primary Human Lung Microvascular Endothelial Cells In Vitro

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