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Review
. 2022 Mar 26;14(7):1388.
doi: 10.3390/nu14071388.

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

Frits A J Muskiet  1 , Pedro Carrera-Bastos  2   3   4 , Leo Pruimboom  5 , Alejandro Lucia  6   7   8 , David Furman  9   10   11   12
Affiliations
Review

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

Frits A J Muskiet et al. Nutrients. .

Abstract

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.

Keywords: COVID-19; SARS-CoV-2; SOCS; interferon; leptin; metaflammation; obesity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the immune response and its dysregulation by metaflammation and SARS-CoV-2. The virus is recognized by pattern recognition receptors (PRR). PRRs are located on the membrane and in the cytoplasm. Through the secretion of cytokines, the infected cell warns other cells to inhibit virus multiplication and spreading (via interferons; IFN-I and -III) and initiate an inflammatory response (via inflammatory cytokines such as TNF-α and IL-6). Signal transduction by cytokines takes place via a cytokine receptor and the Janus kinase/Signal Transducer and Activator of Transcription protein (JAK/STAT) pathway. This pathway creates its own boundary by also expressing the proteins “Suppressor of Cytokine Signaling 1 and 3” (SOCS1/3). These inhibit the JAK/STAT pathway via negative feedback. Metaflammation is characterized by chronic low-grade inflammation. In obesity, the inflamed adipose tissue chronically secretes pro-inflammatory cytokines, including leptin. Leptin and insulin resistance are generated through the inhibition of the JAK/STAT pathway by expression of SOCS1/3. Therefore, in metaflammation, there is already a brake on cytokine signaling before infection. The RNA of SARS-CoV-2 contains codes for non-structural (Nsp) proteins and “accessory” proteins. Infected cells express these proteins. They inhibit the induction and activation of IFN-I. The virus also causes the expression of SOCS1/3. The inhibition of IFN-I signaling by the virus, virus-mediated induction of SOCS1/3, and the preexisting elevation of SOCS1/3 in metaflammation, collectively cause late and initially weak IFN-I and -III responses, and a strong multiplication and spreading of the virus. Major damage is caused by the virus and the immune system. The resulting immune system overreaction, cytokine storm and hypercoagulation are hallmarks of a severe COVID-19 course.
Figure 2
Figure 2
Schematic representation of immune response leading to (a) mild COVID-19 and (b) severe COVID-19. (a) Mild COVID-19 produces an early and robust type I interferon response. This limits the multiplication of the virus and its spreading. There is an adequate T-cell response and antibody formation. This type of response is characteristic of young people and also occurs when they are exposed to a low amount of virus. (b) In severe COVID-19, the type I interferon response is delayed. This gives the virus the chance to multiply and spread quickly. There is also an inadequate T cell response with low T cell numbers. Patients with severe COVID-19 achieve higher peak antibody titers and at a later time. This type of response is characteristic of the elderly and persons with metaflammation in general. It also occurs when they are exposed to a high viral load. Adapted by permission from Springer Nature: Nature Reviews Immunology (The First 12 Months of COVID-19: A Timeline of Immunological Insights, Carvalho, T.; Krammer, F.; Iwasaki, A., 2021) [132], available at https://www.nature.com/articles/s41577-021-00522-1 (License Number: 5254880681651, accessed on 23 February 2022).
Figure 3
Figure 3
Cytokine signaling via the JAK/STAT pathway. A cytokine, such as leptin, binds to its receptor on the plasma membrane. The cytokine receptor is associated with the Janus kinase (JAK; “Just Another Kinase”). JAK phosphorylates two receptor tyrosines, after which JAK is recognized by STAT (Signal Transducer and Activator of Transcription). Subsequently, STAT is also phosphorylated by JAK. Two phosphorylated STATs form a dimer. The STAT dimer acts as a transcription factor. It binds to the promoter parts of genes affected by that cytokine (“target genes”). These genes are then transcribed into mRNA (DNA to mRNA) and translated into proteins (mRNA to protein). Proteins expressed via this JAK/STAT pathway have functions in proliferation, differentiation, growth and apoptosis. Together they form the products of the “Cytokine Inducible Genes” (CIG). Suppressor Of Cytokine Signaling (SOCS) is also a CIG product. SOCS inhibits the JAK/STAT pathway and thus cytokine signaling. This creates a negative feedback loop. Modified from Morris, Kershaw and Babon [147].
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