As a matter of fat: Leptin, monocyte hyperactivation, and COVID-19

Graphical Abstract

Discussion on leptin's effects on the pathophysiology of COVID-19 and its potential as a biomarker for this disease.

Graphical Abstract.

Despite the approval by regulatory agencies of different vaccines against SARS-CoV-2, the coronavirus disease 2019 (COVID-19) pandemic continues to represent the worst health threat worldwide and to cause morbidity and mortality with ∼2,000,000 death cases reported to WHO by January 2021 (https://covid19.who.int). Since the discovery of the SARS-CoV-2 as the etiologic agent of COVID-19 in early 2020, the scientific and medical community has questioned whether some individuals could manifest worse symptoms when infected by this virus and develop a more critical disease with negative outcomes. Thus, there has been an intense scrutiny of biological determinants and mechanisms that could underlie severe forms of COVID-19 to provide support for precision medicine and clinical management of patients.

Initial studies reported that patients with severe COVID-19 had increased blood concentrations of cytokines (like IL-6, IL-1β, and TNF-α), chemokines (e.g., CXCL-10, MCP-1, IL-8), cell activation markers (e.g., CD14, selectins), and acute phase response proteins (e.g., S100A), highlighting that monocyte/macrophage (MΦ) hyperactivation and inflammatory phenotype(s) contribute to the pathogenesis and progression of COVID-19.^1–4 Indeed, studies aimed at blocking or reprogramming the host immune and inflammatory response in patients with SARS-CoV-2 infection have been undertaken in order to test strategies for mitigating the progression of COVID-19 that could be ancillary or vicarious for vaccines.

From multiple studies and clinical observations, it appears also clear that chronic inflammatory conditions, overweight, and lipid disorders, including obesity, type 2 diabetes, and coronary artery disease, are risk factors for severe illness from COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov). A recent metanalysis from 75 studies used to identify the relationship of obesity and COVID-19 highlights that obese individuals are at >46% higher risk for SARS-CoV-2 infection, >113% for hospitalization, and >48% for death.⁵ Mechanistic links between COVID-19 risk and obesity proposed by the authors of this metanalysis include immune impairment, underlying adipose inflammation, and metabolic disturbances. Notably, these (and many other) syndromes linked to high-risk status in COVID-19 are also pathophysiologically dependent on monocyte/MΦ dysregulation.

Monocyte/MΦ, the master cell in inflammation and resolution, are important effectors of metabolic homeostasis and immunity in viral infections.⁶ In a recent paper on this issue of JLB, Wang and colleagues reported on an investigation aimed at clarifying the characteristics of inflammatory cytokine-profile and monocyte/MΦ responses to SARS-CoV-2 infection in patients with severe symptoms. The authors carried out a class comparison and longitudinal study on COVID-19, measuring 174 cytokines in peripheral blood from a small cohort of patients. Using this approach, they identified discrete clusters of soluble factors associated with inflammation and immune response segregating patients based on disease severity. Among these, the authors found leptin as a plasma protein significantly increased in severe and mild COVID-19 and that leptin had a prognostic power for disease progression superior to that of other classic inflammation markers (IL-6 and CXCL-10) (Fig. 1).⁷

FIGURE 1.

Model for leptin-mediated monocyte hyperactivation in COVID-19 in obese people. Population screening indicates that high plasma leptin in overweight people is a classifier and predictor of COVID-19 severity. Leptin (likely secreted by adipocytes) induces NF-κB/STAT3 activation, acquisition of a M1 inflammatory phenotype, and cytokine hypersecretion in monocytes. These results suggest that higher leptin levels in overweight patients further activate monocytes resulting in amplified immune responses in COVID-19. Remaining questions are if SARS-CoV-2 directly infects adipocytes, thus triggering leptin secretion or if adipose tissue resident infected monocytes release paracrine factors that stimulate adipocytes to produce leptin. The illustration was created with SERVIER Medical Art templates (https://smart.servier.com/)

Leptin (from the ancient Greek word “leptos” for “thin”) is a small (167 amino acid) adipokine mainly secreted by white adipose tissue that was originally considered as a master regulator of energy homeostasis, metabolism, and neuroendocrine functions.⁸ However, leptin has pleiotropic actions on the immune system. Leptin directly regulates the production of several cytokines, chemokines, and interferons, influences the Th1/Th2 balance, and modulates phagocytic function of macrophages.⁹

The study by Wang and colleagues point at these cells in the context of COVID-19 providing evidence that monocytes expressing the activation marker CD80 are increased in peripheral blood from patients with severe COVID-19 and that this can be mediated directly by leptin at concentrations found in plasma.⁷ This is corroborated by in vitro treatments of human monocytes with leptin, which resulted in an activation of the NF-κB/STAT3 pathways and in an increase in CD80, TNF-α, CD86, and other inflammatory proteins.⁷ Overall, this study provides interesting insights into the mechanisms underlying COVID-19 progression, suggesting that leptin can directly contribute to the pathophysiology of this disease by modulating host monocyte intracellular signaling, inflammatory responses, and phenotypes (Fig. 1). Whether leptin could represent a biomarker useful in clinical settings remains to be established in a prospective, multicenter study.

This study also opens other exciting questions (Fig. 1):

1. Are some of the many inflammatory mediators driven by SARS-CoV-2 responsible for the increase in leptin production or does SARS-CoV-2 per se stimulates leptin production in adipocytes or adipose-tissue resident monocyte/macrophages in a feed-forward loop?

2. The Authors identified a subset of large monocytes secreting IL-6, TNF-α, and IL-10 (not seen in other viral infections) being increased in patients with COVID-19. It would be important to determine if these large monocytes (considered bona fide pro-inflammatory during SARS-CoV-2 infection) are present in a higher percentage in obese individuals before or after SARS-CoV-2 infection.

3. Other chronic inflammatory metabolic, cerebrovascular, and neurological diseases are associated with increased odds of severe COVID-19. Studies of the interaction between SARS-CoV-2 infection, metabolism, and inflammation would be worth to determine whether findings of Wang and colleagues are similar in COVID-19 patients with other comorbidities given the multiple biological functions of leptin in several tissues and organs.