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

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.

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.