COVID-19 : obesity – fat cells can set off a complex inflammatory chain reaction

When obesity occurs, a person’s own fat cells can set off a complex inflammatory chain reaction that can further disrupt metabolism and weaken immune response – potentially placing people at higher risk of poor outcomes from a variety of diseases and infections, including COVID-19.

A study laying out the details of this newly revealed cellular process was led by scientists at Cincinnati Children’s and the University of Cincinnati College of Medicine and was published online June 2, 2020, in Nature Communications.

The team reports that type I interferons, a class of substances produced by immune cells also are produced by fat cells called adipocytes. These interferons drive a constant low-level, chronic immune response that amplifies “vigor” to a cycle of inflammation within white adipose tissue (WAT).

More commonly known as white fat, this is the type of fat that expands to form most of the unwanted bulges around our thighs, arms and bellies.

This inflammation, in turn, appears to drive a cascade of cellular responses that promotes obesity-related disease, especially type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).

“Our novel study reveals how Type I Interferon sensing by adipocytes uncovers their dormant inflammatory potential and exacerbates obesity-associated metabolic derangements.

Further, our findings highlight a previously underappreciated role for adipocytes as a contributor to the overall inflammation in obesity,” says Senad Divanovic, Ph.D., corresponding author and a researcher in the Division of Immunobiology at Cincinnati Children’s.

Health risks of obesity include poor infection outcomes

Obesity affects more than 600 million people worldwide – and the US has the highest average adult body mass index (BMI) of all high-income countries. By 2030, roughly half of the U.S. population could become obese.

Long known as a major risk factor for type 2 diabetes, NAFLD, cardiovascular disease, and diverse cancers, obesity also has been linked with elevated susceptibility and risk of developing serious complications to infection.

Obesity also was an independent risk factor for severity and mortality in the 2009 H1N1 influenza pandemic, and is a risk for hospital admission and poor outcomes among those infected in the current COVID-19 pandemic.

Many studies have shown that obesity is much more complicated than simply eating too much or not getting enough exercise. Previous work has shown that obesity also reflects the outcome of various disruptions to how the body converts food into energy for our cells.

However, only recently have scientists begun to suspect that these excess calories could reshape fat cell behavior to affect the immune system.

Adipocytes revealed as new target for type 1 interferons

The new study shows how type 1 interferons operate along an axis of interaction with IFNa receptors (IFNAR) to trigger a vicious cycle of inflammation. Among the effects: changes in expression of several genes associated with inflammation, glycolysis and fatty acid production.

For example, mice fed an obesity-inducing diet displayed an augmented type I IFN signature including increases in Ifnb1, Ifnar1, Oas1a, and Isg15 gene expression, the team reported.

Importantly, many of the metabolic changes documented in mice were found to be conserved in human adipocytes.

This activity was unexpected, because until now most scientists have studied type 1 interferons in relation to viral infections and immune cell function.

“Our observations suggest that the type I Interferon axis can alter adipocyte core inflammatory programming to converge them closer to that of an inflammatory immune cell.

Additionally, type I Interferons modify the metabolic circuit of adipocytes, which to our knowledge is the first depiction of immune-mediated modulation of adipocyte core metabolism,” Divanovic says.

What’s next?

Further investigation continues into the specific mechanisms that type I Interferons employ to modify adipocyte core metabolism. In addition, researchers continue to study the full extent of how adipocytes can “mimic” inflammatory immune cell capabilities.

“These findings directly impact an extensive number of patients, both adult and pediatric,” Divanovic says.

Beyond diabetes and NAFLD, the interplay between obesity and the immune system appears to increase risk of preterm birth and may reduce the body’s ability to fight off infections—including viruses such as COVID-19.

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Physicians are trying to establish the risk factors that might affect the spread of the novel SARS-CoV-2 virus and those that might worsen the prognosis of hospitalised patients [1]. Among those, it seems that the new pandemic is complicated by an older one, which is already well-defined, that is obesity.

Being overweight and obesity are defined as having abnormal or excessive fat accumulation, respectively, that may impair health [2]. Obesity has nearly tripled worldwide since 1975, hence it has been characterised as a pandemic.

In 2016, 39% of adults worldwide (more than 1.9 billion people) were overweight and 13% were obese (over 650 million people), whereas in 2018, 40 million children under the age of 5 were overweight or obese. Obesity is a major health concern, mainly because of its side-effects in humans and its associated morbidity and mortality rates [3].

On the other hand, according to the World Obesity Federation, obesity-related conditions seem to worsen the effect of SARS-CoV-2; indeed, the Centres for Disease Control and Prevention (CDC) reported that “people with heart disease and diabetes are at higher risk of Covid-19 (SARS-CoV-2) complications and that severe obesity (body mass index [BMI] of 40 or higher) poses a higher risk for severe illness” [4].

We therefore hypothesised that there might be a pathophysiological link that could explain the fact that obese patients are prone to present with SARS-CoV-2 complications.

Looking back on similar infectious outbreaks, during the 2009 H1N1 pandemic, obesity was recognized as an independent risk factor for complications from influenza [5], thus it is not surprising that obesity is a potential independent risk factor for SARS-CoV-2 as well.

Obese individuals have shown diminished protection from influenza immunization, since – despite being vaccinated – obese recipients are 2–3 times more prone to suffer from infection compared to non-obese.

Thus, the potential implications for obesity in the SARS-CoV-2 outbreak should be elucidated [6]. We hereby present “mechanistic” obesity-related problems that aggravate SARS-CoV-2 infection as well as tentative molecular links between obesity and SARS-CoV-2 infection.

“Mechanistic” problems
Obese patients often need bariatric hospital beds, which may be scarce and are definitely more difficult to position and transport by nursing staff. In these patients proper imaging diagnosis may be compromised (there are weight limits for the beds of imaging equipment).

Obese patients are very prone to diminished airway flow, due to limited truncal expansion, making it difficult to ease the airflow (and increasing susceptibility to poor breathing) [7]; oxygen consumption and respiratory potential can be seriously affected and predispose to infection and the need for more oxygen support [7]. Finally these patients pose a serious challenge for intubation (since the additional adipose tissue on the larynx makes intubation more difficult).

Molecular pathways
So far, hyperglycemia was noted in 51% of cases with the novel SARS-CoV-2 infection [8]. Hyperglycemia was also observed in patients with SARS in 2003, caused by a different type of coronavirus (SARS-CoV), partly because the virus leads to transient impairment of pancreatic islet cell function [9].

Dipeptidyl peptidase 4 (DPP4; an enzyme responsible for the degradation of incretins such as glucagon like peptide-1, GLP-1) serves as receptor for MERS CoV (Middle eastern respiratory syndrome) and human coronavirus EMC [9]. Moreover, hyperglycemia might also be caused by endogenous stress-induced glucocorticoid hypersecretion [9].

Recent reports have shown an increased inflammatory environment, leading to a exacerbated cytokine profile (cytokine storm) in patients with SARS-CoV-2 disease [10], mainly manifested by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemo-attractant protein 1 (MCP1), macrophage inflammatory protein 1-α, and tumour necrosis factor-α (TNFα).

Earlier investigations of SARS-CoV infection, showed that it mediated its actions via suppression of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, resulting in lower Cox-2 (cyclooxygenase-2) expression (thus easing inflammation) [11].

In MERS-CoV infection, translocation of NF-κB to the nucleus leads to a cascade of pro-inflammatory cytokines [12]. Among all interleukins, IL-6 was found to be associated with a highly pathogenic SARS-CoV-2 infection, due to enhanced virus replication mainly in the lower respiratory tract [13].

Moreover, levels of ferritin and IL-6 were statistically significantly higher in non-survivors compared to survivors in the recent outbreak of SARS-CoV-2 in China [14].

Obesity represents a state of low-grade inflammation, with various inflammatory products directly secreted by adipose tissue. Hyperplastic or hypertrophied adipose tissue releases inflammatory cytokines (TNFα, IL-1, IL-6, IL-10), transforming growth factor-b (TGF-b), adipokines (leptin, resistin, adiponectin), MCP-1 (monocyte chemoattractant protein-1), CXCL5 (C-X-C motif chemokine ligand 5), hemostatic proteins (plasminogen activator inhibitor-1; PAI-1), proteins affecting blood pressure, (angiotensinogen) and angiogenic molecules (vascular endothelial growth factor; VEGF) [15].

The main adipose tissue-derived inflammatory cytokines are TNFα, IL-1, IL-6, which altogether comprise an “inflammatory triad”. Levels of TNFα are increased in obesity, indicating a role for this cytokine in the obesity-associated inflammation and particularly in insulin resistance and diabetes.

Interleukin-1 can lead to the activation of transcription factors such as NF-kB, promoting inflammatory signalling overexpression of the angiogenic factor VEGF (vascular endothelial growth factor), while increased levels of IL-6 in obesity play a key role in inflammation-associated carcinogenesis, via the JAK/STAT (Janus kinase signal transducer and activator of transcription) signalling pathway [16].

Features of inflammation are consequent hypoxia and ischemia (hypoxia is the lack of oxygen in the blood or in adipose tissue, while ischemia is caused by an inadequate blood flow).

Both hypoxia and ischemia drive to a state of oxidative stress, further stimulating the secretion of inflammatory proteins and reactive oxygen radicals (radical oxygen species, ROS) that damage mitochondrial functionality and DNA [17].

Thus, the hypertrophic, and at the same time hypoxic, white adipocytes change their normal protein synthesis and shift towards the production of cytokines and inflammatory proteins, leading to insulin resistance, type 2 diabetes mellitus (T2DM), metabolic syndrome, atherosclerosis and arterial hypertension, while recent evidence favours their implication in various types of cancer [18].

Among the various products of adipose tissue, is leptin. Leptin is a cytokine that serves as an alarm (inhibition signal) to the body, in order to reduce caloric consumption and return to a steady state. Initially thought as the cure for obesity in a recombinant form, leptin was found to face serious resistance in the body of the obese.

Although in obesity leptin levels are increased, the action of leptin per se is reduced, in a analogous way to insulin’s action in patients with T2DM. Zhang et al. suggested that leptin resistance could aggravate the outcome of the patients during the 2009 A (H1N1) pandemic influenza, since leptin exerts positive effects in B cell maturation, development and function, along with alterations of lymphocytes and inhibition of CD8+ T cell response and impaired memory T cell response, seen in obesity, which both under normal circumstances would act against the virus [19].

Hyperglycaemia or established T2DM (usually associated with obesity) have shown to be independent predictors of mortality and morbidity in patients with SARS [9]. A proposed mechanism is that in SARS the noted enhanced release of cytokines leads to a state of increased metabolic inflammation.

Especially in the case of SARS-CoV-2, a cytokine storm (elevated levels of inflammatory cytokines) has been suggested to be implicated in the multi-organ failure in patients with severe disease.

Adipose tissue expresses most of the components of the renin angiotensin aldosterone system (RAAS), such as angiotensinogen (AGT), angiotensin converting enzymes (ACE and ACE2) and their receptors, their mRNA being reduced in starvation and increased in overfeeding.

Angiotensin (AT) II promotes prostacyclin synthesis, differentiation of the adipocytes and lipogenesis. Inside the adipose cell, ACE is stimulated towards the conversion of angiotensin I to angiotensin II, thus further stimulating the RAAS axis, the production of aldosterone and the rise in blood pressure [20].

Various reports have included arterial hypertension as a risk factor for severity of SARS-CoV-2, possibly related to ACE2 via the actions of ACE-inhibitors and AT receptor blockers (ARB), given for the treatment of hypertension (ACE2 acts as receptor that indeed seems to facilitate the entry of coronavirus into cells) [21].

Of note, the percentage of patients with hypertension suffering from SARS-CoV-2 is roughly the same as the prevalence of hypertension in the same age group, regardless of SARS-CoV-2 infection, which means that hypetension is not a risk factor per se, but rather a pre-existing disease at that age group [21].

Overall data do not fully support the notion that discontinuation of these medications is beneficial, since other reports in animals show that elevated ACE2 expression might exert potentially protective pulmonary and cardiovascular effects [21] (Fig. 1 ).

Among the limitations of this work we have to note that although we presented possible and plausible links among the inflammatory and metabolic aspects of obesity and SARS-CoV-2 infection (based on the available – and rapidly evolving – literature), further relevant research is warranted.

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More information: Calvin C. Chan et al, Type I interferon sensing unlocks dormant adipocyte inflammatory potential, Nature Communications (2020). DOI: 10.1038/s41467-020-16571-4

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