key: cord-1007561-e5zib28k
authors: Briand‐Mésange, Fabienne; Trudel, Stéphanie; Salles, Juliette; Ausseil, Jérôme; Salles, Jean‐Pierre; Chap, Hugues
title: Possible Role of Adipose Tissue and Endocannabinoid System in COVID‐19 Pathogenesis: Can Rimonabant Return?
date: 2020-05-28
journal: Obesity (Silver Spring)
DOI: 10.1002/oby.22916
sha: bbee33f52c2cc7dccc77097327ea5cf8beb37c9f
doc_id: 1007561
cord_uid: e5zib28k

This is the main conclusion of a recent study describing a strong relationship between the degree of obesity and the severity of COVID‐19 infection. Obesity has various negative consequences relative to the course of COVID‐19, including adverse effects on lung physiology, and induces comorbidities such as type II diabetes or hypertension. However, additional mechanisms involving the low‐grade inflammatory state accompanying obesity can also be suggested.

This article is protected by copyright. All rights reserved "Obesity is an Independent Risk Factor for Severe COVID-19" This is the main conclusion of a recent study describing a strong relationship between the degree of obesity and the severity of COVID-19 infection (1) . Obesity has various negative consequences relative to the course of COVID-19, including adverse effects on lung physiology, and induces comorbidities such as type II diabetes or hypertension. However, additional mechanisms involving the low-grade inflammatory state accompanying obesity can also be suggested (1) .

A main medical problem raised by COVID-19 is the hyperinflammation accompanying the most severe forms of disease, characterized by acute respiratory distress syndrome and multiorgan failure in a general context of life-threatening cytokine storm (2) . In obesity, adipose tissue expansion is accompanied by infiltration of macrophages producing inflammatory cytokines such as TNF, IL-1 or IL-6. There is a significant correlation between body mass index (BMI) and the number of macrophages present in adipose tissue, which can be as much as 25 % of adipocyte cell numbers (3) . Although inflammation accompanying obesity appears as a low grade chronic inflammatory state, one can question whether the huge numbers of immune cells present in adipose tissue of patients with obesity might not represent a kind of time bomb contributing to the cytokine storm observed in COVID-19. Despite perturbing data suggesting a paradoxical protection of obesity against bacterial sepsis (4), the opposite has been observed for influenza pneumonia (4) and COVID-19 (1).

Considering the above data, we put forward the hypothesis that reducing the inflammatory potential of adipose tissue in patients with obesity might decrease the risk of developing severe complications of COVID-19. This goal could be achieved by weight loss (3), but this does not correspond to the emergency of the situation, which might better benefit from an appropriate pharmacological intervention. Adipose tissue development is under control of endocannabinoid system, which involves at least two receptors (CB1 and CB2), endocannabinoid ligands (mainly anandamide and 2-arachidonoyl glycerol), as well as various proteins involved in endocannabinoid metabolism (5) . CB1 is particularly abundant in brain, where it is responsible for the psychotropic effects of (−)-trans-Δ⁹-tetrahydrocannabinol, whereas CB2 is mainly present in immune cells (5) . CB1 is also expressed in peripheral tissues such as liver, skeletal muscle, pancreatic islets and adipose tissue, where it regulates energy metabolism (5) . In brief, obesity is accompanied by an elevated endocannabinoid tone, where stimulation of central CB1 promotes increased

This article is protected by copyright. All rights reserved food uptake, whereas peripheral CB1 induces lipogenesis and fat accumulation in adipose tissue (5) . This led to the development of CB1 antagonists aimed at reducing obesity by decreasing endocannabinoid tone. One of them (SR141716 or rimonabant, an inverse agonist of CB1 acting on both central and peripheral CB1) was effective at reducing body weight (6) . However, the central action of rimonabant also induced serious mood disorders, which led to the withdrawal of the marketing authorization of rimonabant in European Union (6).

The first clinical trials on rimonabant were essentially focused on cardiovascular risk factors typical of obesity. However, a number of preclinical studies were developed in the last 15 years, one of the latest describing the molecular mechanisms underlying the inhibition by rimonabant of inflammation accompanying diet-induced obesity in mice (7). In addition, in a rat model of bacterial sepsis, rimonabant was shown to reduce mortality and to correct vascular hyperreactivity (8) , which might be relevant in the context of the worse clinical outcomes associated with COVID-19 (2).

Second and third generation CB1 antagonists unable to cross the blood-brain barrier were developed to avoid side effects related to inhibition of central CB1, and have been shown to display similar anti-obesity and anti-inflammatory effects (9) . However, despite a few preliminary clinical trials, none of these drugs reached the level of clinical translation, making it difficult to emphasize their use in the emergency context of COVID-19 outbreak (9) . Thus, rimonabant appears as the only drug immediately available for clinical trials, together with taranabant, which also reached phase III clinical trials with similar secondary effects (10).

In view of the dramatic consequences of COVID-19, the time required to obtain vaccines or to reach herd immunity has concentrated hope on drug-repositioning, including antiviral and anti-cytokine drugs as well as drug combination therapy. We suggest rimonabant as an interesting avenue to reduce the infection severity occurring in patients with visceral obesity. Indeed, the weight-loss-independent increase of adiponectinemia induced by rimonabant suggested a direct effect of the drug on adipocytes from

This article is protected by copyright. All rights reserved abdominal tissue (6) . Interaction of rimonabant with adipocyte CB1 is thus expected to decrease the inflammatory state of abdominal tissue, in a manner similar to the specific invalidation of adipocyte CB1 (11) . In addition, CB1 blockade was shown to reduce pulmonary inflammation in at least two different preclinical models (12, 13) . This might be particularly relevant in the context of COVID-19, although the opposite was observed in mice infected with respiratory syncytial virus (14) . However, three concerns must be considered. First, the adverse psychiatric effects evoked by rimonabant might not be an intractable difficulty, as long as its administration would be restricted to the acute phase of infection in intensive care units (ICU), where patients are sedated and strictly monitored, thus preventing the risk of anxiety, depression and suicide at this stage. However, for patients treated with rimonabant, sub-acute and chronic psychiatric complications should be carefully monitored, since survivors of critical illness are at risk of persistent psychiatric impairment. Moreover, if the chronic neuropsychiatric sequelae are still unknown for SARS-CoV2, depressed mood, anxiety and traumatic memories were associated with previous coronavirus infections in the long term (15) . So, a psychiatric surveillance should be initiated for patients after ICU discharge and reinforced in case of rimonabant administration. Second, rimonabant was associated with upper respiratory tract infections in adverse event reporting, which is unexplained but should not be a fatal flaw in exploring its use in the context of COVID-19 (16) . A last concern relates to using any anti-inflammatory drug as part of an anti-viral therapy, since reducing inflammation could promote virus spreading by decreasing the level of immune defense. The same choice faced anti-cytokine treatments. We suggest that rimonabant be considered for appropriate clinical trials for COVID-19 patients with, beyond COVID-19, other potential indications in similarly critically ill patients.

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Accepted Article This article is protected by copyright. All rights reserved

The effects of obesity on outcome in preclinical animal models of infection and sepsis: a systematic review and meta-analysis

The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders

Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia

Role of microRNA in CB1 antagonist-mediated regulation of adipose tissue macrophage polarization and chemotaxis during diet-induced obesity

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