Role of leptin in immune modulation and pathophysiology of COVID-19

Leptins belong to a class of adipocyte-originating hormones that have a variety of functions in the regulation of appetite and metabolism, as well as in immune regulation. The lungs are a rich source of leptins.

Study: Leptin in the Respiratory Tract: Is There a Role in SARS-CoV-2 Infection?. Image Credit: Rost9/Shutterstock

A recent review paper in the journal Frontiers in Physiology discusses the role of leptins in infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen that triggered the ongoing coronavirus disease 2019 (COVID-19) pandemic.

What do leptins do?

High leptin levels have been linked to obesity and metabolic dysregulation, including insulin resistance and frank type 2 diabetes mellitus, and cardiovascular diseases. These conditions have been identified as risk markers for severe and critical COVID-19. Leptins are also increased in patients with inflammation, such as sepsis or respiratory infection, non-alcoholic steatosis of the liver, and peripheral artery disease.

Leptins modulate innate and adaptive immune responses within monocytes, macrophages, and other white cells, including T lymphocytes. Monocyte activation by leptin is thought to cause the cytokine storm that underlies the occurrence of acute respiratory distress syndrome (ARDS) and multi-organ dysfunction in COVID-19.

The viral receptor on the target host cells is the angiotensin-converting enzyme 2 (ACE2), which is also expressed at higher levels in the lungs, gut, pancreas, and kidneys, besides the blood vessel walls and fat cells. An increased body mass index is associated with higher levels of ACE2.

A third factor linked to poor outcomes following COVID-19 is gut dysbiosis, with an increased proportion of inflammatory bacteria in the gut accompanied by low-grade chronic inflammation.

The gut microbiome and the lung

The gut microbiota is linked to energy homeostasis in the host, and transplantation of the microbiota is linked to the development of obesity. Higher proportions of Bifidobacterium and Lactobacillus in the gut are linked to plasma leptin levels.

The ability of the innate immune system to recognize commensal bacteria is intimately associated with the modulation of the immune and inflammatory response while averting bacterial entry into the system through the intestinal epithelium and preventing colonization by pathogenic bacteria.

The gut microbiome affects lung health via neural and chemical signals, called the gut-lung axis. For instance, gut dysbiosis is linked to a persistent rise in leptins with leptin resistance via the hypothalamic expression of the suppressor of cytokine signaling 3 (SOCS3) and the suppression of the brain-derived neurotrophic factor (BDNF), with the downregulation of neuropeptides that suppress obesity in the central nervous system.

Gut dysbiosis is associated with lung disease, asthma, and allergic inflammation, while an altered microbiome in the lung is linked to intestinal dysbiosis. Not only are intestinal bacteria seeded into the lung via reflux or aspiration, but some products of the gut microbiota affect the lung microbiome composition and function. Endotoxins from intestinal microbes may travel to the lung to cause inflammation, and such inflammation may, in turn, affect the gut microbiome.

Conversely, short-chain fatty acids (SCFAs) from the intestine, produced from dietary fiber, promote phagocytic dendritic cell migration into the lung while reducing the activation of Th2 effector functionality. This modulates airway inflammation. Lung tissue express SCFA receptors and free fatty acid receptors that mediate baseline immune function in this organ via the interleukin-1β (IL-1β) pathway.

SCFAs also promote leptin production and increase leptin sensitivity

Postbiotics, or microbial components, can modulate localized or systemic inflammation by triggering cascading pathways. Many factors affect leptin sensitivity, including the state of the gut and the diet, mediated by metabolites produced by the gut microbiota from dietary constituents.

Gut microbiota modulations could be a novel therapeutic target to reset leptin sensitivity.”

Leptin and the lung

Leptin seems to be involved in fetal lung maturation and modulates the diameter of the smaller airways. Abnormal leptin synthesis and activity may underlie lung diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, lung cancer, and pulmonary arterial hypertension.

Leptin may protect against respiratory infections, judging by the falling leptin levels as inflammatory markers rise.

Leptin and SARS-CoV-2

In COVID-19, obesity may exacerbate the inflammatory response and promote a poor immune response via altered leptin sensitivity.

Anosmia may be traceable to the leptin-induced alteration in the olfactory epithelium. The presence of high leptin levels in obese patients with COVID-19, compared with controls, and in severe COVID-19 compared with mild cases, indicates that leptin levels are higher in patients with an increased percentage of body fat.

The leptin may mediate the cytokine storm via monocyte activation. The reduction in ACE2 function after it is bound by the virus causes a loss of ACE2-induced leptin inhibition, further promoting the hyper-inflammatory response in the lungs seen more commonly in obese COVID-19 patients. Thus, an impaired immune response accompanied by intense systemic inflammation leads to critical or fatal outcomes in this group of patients, possibly due to the role of leptins.

What are the implications?

Since leptin reduces antibody production and class switching of immunoglobulin antibodies, this could impair the immune response to SARS-CoV-2. The occurrence of respiratory failure occurs after a lapse of one to two weeks from the onset of symptoms. This could be exploited to counteract the inflammatory pathway mediated by leptin production.

The presence of the leptin receptor in the lung and leptin production in this organ seems to indicate that this hormone is involved in lung health. Especially in COVID-19, the action of leptin in preventing the release of anti-inflammatory mediators can reduce the normal immune response, leading to the progression or persistence of the infection.

In conclusion, obesity-associate chronic inflammation impairs immune function and increases ACE-2 expression resulting in an increased disease severity and worse clinical outcome in obese subjects with COVID-19.”

Further studies should unravel the respective roles of the gut microbiome and leptin, so as to help develop new preventives and therapeutics for this condition.