COVID-19 Severity in Obesity: Leptin and Inflammatory Cytokine Interplay in the Link Between High Morbidity and Mortality

Abstract

Obesity is one of the foremost risk factors in coronavirus infection resulting in severe illness and mortality as the pandemic progresses. Obesity is a well-known predisposed chronic inflammatory condition. The dynamics of obesity and its impacts on immunity may change the disease severity of pneumonia, especially in acute respiratory distress syndrome, a primary cause of death from SARS-CoV-2 infection. The adipocytes of adipose tissue secret leptin in proportion to individuals' body fat mass. An increase in circulating plasma leptin is a typical characteristic of obesity and correlates with a leptin-resistant state. Leptin is considered a pleiotropic molecule regulating appetite and immunity. In immunity, leptin functions as a cytokine and coordinates the host's innate and adaptive responses by promoting the Th1 type of immune response. Leptin induced the proliferation and functions of antigen-presenting cells, monocytes, and T helper cells, subsequently influencing the pro-inflammatory cytokine secretion by these cells, such as TNF-α, IL-2, or IL-6. Leptin scarcity or resistance is linked with dysregulation of cytokine secretion leading to autoimmune disorders, inflammatory responses, and increased susceptibility towards infectious diseases. Therefore, leptin activity by leptin long-lasting super active antagonist's dysregulation in patients with obesity might contribute to high mortality rates in these patients during SARS-CoV-2 infection. This review systematically discusses the interplay mechanism between leptin and inflammatory cytokines and their contribution to the fatal outcomes in COVID-19 patients with obesity.

Keywords: COVID-19; cytokine; inflammation; leptin; mortality; obesity.

Figure 1

Schematic representation of extra pulmonary viral shedding and adipose tissue (AT) inflammation in COVID-19 patients with obesity. Angiotensin-converting enzyme 2 (ACE2) receptor in the lung epithelial cells recognizes the COVID-19 spike protein and the virus with receptor taken into the cells by receptor-mediated endocytosis. Then, viral RNA integrates into the host genome for viral replication and assembly. The free viral particles inside the host cell are released through exocytosis to infect healthy cells. Extracellular vesicles (EVs) containing viral proteins, and ACE2 receptors are also carried over to cells of extra pulmonary fatty visceral organs. The fatty adipose tissue in patients with obesity is a link to extra pulmonary viral shedding through the ACE2 expressing adipocytes. The adipocytes in the fatty AT of visceral organs (liver, heart, and kidney) act as a reservoir for viral replication and assembly. Apoptotic and necrotic death of the virus inside the adipocytes leads to meta-inflammation and subsequent fat embolism syndrome (FES) in COVID-19 patients with obesity.

Figure 2

Schematic representation of the effects of Hypoxia and Leptin on pro-inflammatory cytokine response in adipose tissue (AT). The effect of low O₂ tension on the production of adipokines in hypoxia condition. The adipocyte in the adipose tissue release leptin, which induces the release of pro-inflammatory cytokine by endocrine, paracrine, and autocrine in the AT. Leptin induces Th1 cells, and it inhibits T regulatory cells (Treg cells) and induces Th17 cells differentiation to produce IL-2 and IFN-γ. Leptin directly activates macrophages, dendritic cells (DC), and natural killer (NK) cells to produce pro-inflammatory cytokines, such as IL-6, IL-1, and TNF-α. Adipocyte-derived leptin induces the adipocytes to produce pro-inflammatory cytokines (IL-6, IL-1, and TNF-α) through autocrine signaling.

Figure 3

Signal transduction cascades of leptin and IL-6 interplay in inflammation. Leptin binding to the long-form leptin receptor (LRb or gp130R) results in the activation of the Janus kinase 2 (JAK2) signaling pathway by autophosphorylation, which subsequently phosphorylates tyrosine 985 and 1138 residues of the intracellular receptor tail. The phosphorylated Tyr 1138 activates the transcription factor STAT3. The activated JAK/STAT3 activates IRS1 and PI3K downstream signaling pathway, which recruits NF-kB complex (P50, P65/c-Rel, IkB), resulting in the transcription of IL-6 expressing genes in the nucleus. JAK/STAT3 directly activates PI3k inhibits apoptosis by the activation of anti-apoptotic factors (BCL-2, BCL-XL). Pleiotropic leptin and IL-6 follow similar signaling through gp130R and gp130Rβ, respectively. Leptin-induced IL-6 binding to the gp130Rβ results in the activation of JAK/STAT followed by the activation of PKA- and MAPK-mediated Elk phosphorylation. The phosphorylated Elk induces the transcription factors for TNF-α and IL-1. IL-6–mediated TNF-α and IL-1 induce the production of leptin from adipocytes.