The shades of grey in adipose tissue reprogramming.

The adipose tissue (AT) has a major role in contributing to obesity-related pathologies through regulating systemic immunometabolism. The pathogenicity of the AT is underpinned by its remarkable plasticity to be reprogrammed during obesity, in the perspectives of tissue morphology, extracellular matrix (ECM) composition, angiogenesis, immunometabolic homoeostasis and circadian rhythmicity. Dysregulation in these features escalates the pathogenesis conferred by this endometabolic organ. Intriguingly, the potential to be reprogrammed appears to be an Achilles' heel of the obese AT that can be targeted for the management of obesity and its associated comorbidities. Here, we provide an overview of the reprogramming processes of white AT (WAT), with a focus on their dynamics and pleiotropic actions over local and systemic homoeostases, followed by a discussion of potential strategies favouring therapeutic reprogramming. The potential involvement of AT remodelling in the pathogenesis of COVID-19 is also discussed.

COVID-19 and Obesity: Role of Ectopic Visceral and Epicardial Adipose Tissues in Myocardial Injury.

In March 2020, the WHO declared coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic. Obesity was soon identified as a risk factor for poor prognosis, with an increased risk of intensive care admissions and mechanical ventilation, but also of adverse cardiovascular events. Obesity is associated with adipose tissue, chronic low-grade inflammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of pro-inflammatory cytokines. However, to implement appropriate therapeutic strategies, exact mechanisms must be clarified. The role of white visceral adipose tissue, increased in individuals with obesity, seems important, as a viral reservoir for SARS-CoV-2 via angiotensin-converting enzyme 2 (ACE2) receptors. After infection of host cells, the activation of pro-inflammatory cytokines creates a setting conducive to the "cytokine storm" and macrophage activation syndrome associated with progression to acute respiratory distress syndrome. In obesity, systemic viral spread, entry, and prolonged viral shedding in already inflamed adipose tissue may spur immune responses and subsequent amplification of a cytokine cascade, causing worse outcomes. More precisely, visceral adipose tissue, more than subcutaneous fat, could predict intensive care admission; and lower density of epicardial adipose tissue (EAT) could be associated with worse outcome. EAT, an ectopic adipose tissue that surrounds the myocardium, could fuel COVID-19-induced cardiac injury and myocarditis, and extensive pneumopathy, by strong expression of inflammatory mediators that could diffuse paracrinally through the vascular wall. The purpose of this review is to ascertain what mechanisms may be involved in unfavorable prognosis among COVID-19 patients with obesity, especially cardiovascular events, emphasizing the harmful role of excess ectopic adipose tissue, particularly EAT.

Cardiac adipose tissue volume and IL-6 level at admission are complementary predictors of severity and short-term mortality in COVID-19 diabetic patients.

BACKGROUND: COVID-19 diabetic adults are at increased risk of severe forms irrespective of obesity. In patients with type-II diabetes, fat distribution is characterized by visceral and ectopic adipose tissues expansion, resulting in systemic inflammation, which may play a role in driving the COVID-19 cytokine storm. Our aim was to determine if cardiac adipose tissue, combined to interleukin-6 levels, could predict adverse short-term outcomes, death and ICU requirement, in COVID-19 diabetic patients during the 21 days after admission. METHODS: Eighty one consecutive patients with type-II diabetes admitted for COVID-19 were included. Interleukin-6 measurement and chest computed tomography with total cardiac adipose tissue index (CATi) measurement were performed at admission. The primary outcome was death during the 21 days following admission while intensive care requirement with or without early death (ICU-R) defined the secondary endpoint. Associations of CATi and IL-6 and threshold values to predict the primary and secondary endpoints were determined. RESULTS: Of the enrolled patients (median age 66 years [IQR: 59-74]), 73% male, median body mass index (BMI) 27 kg/m2 [IQR: 24-31]) 20 patients had died from COVID-19, 20 required intensive care and 41 were in conventional care at day 21 after admission. Increased CATi and IL-6 levels were both significantly related to increased early mortality (respectively OR = 6.15, p = 0.002; OR = 18.2, p < 0.0001) and ICU-R (respectively OR = 3.27, p = 0.01; OR = 4.86, p = 0.002). These associations remained significant independently of age, sex, BMI as well as troponin-T level and pulmonary lesion extension in CT. We combined CATi and IL-6 levels as a multiplicative interaction score (CATi*IL-6). The cut-point for this score was ≥ 6386 with a sensitivity of 0.90 and a specificity of 0.87 (AUC = 0.88) and an OR of 59.6 for early mortality (p < 0.0001). CONCLUSIONS: Cardiac adipose tissue index and IL-6 determination at admission could help physicians to better identify diabetic patients with a potentially severe and lethal short term course irrespective of obesity. Diabetic patients with high CATi at admission, a fortiori associated with high IL-6 levels could be a relevant target population to promptly initiate anti-inflammatory therapies.

High prevalence for obesity in severe COVID-19: Possible links and perspectives towards patient stratification.

It is becoming obvious that in addition to aging and various hearth pathologies, excess of body weight, especially obesity is a major risk factor for severity of COVID-19 infection. Intriguingly the receptor for SARS-CoV-2 is ACE2, a member of the angiotensin receptor family that has a relatively large tissue distribution. This observation likely explains the multitude of symptoms that have been described from human patients. The adipose tissue also expresses ACE2, suggesting that adipocytes are potentially infected by SARS-CoV-2. Here we discuss some of the potential contribution of the adipose tissue to the severity of the infection and propose some aspects of obese patients metabolic phenotyping to help stratification of individuals with high risk of severe disease.

Review: Obesity and COVID-19: A Detrimental Intersection.

Obesity has been recognized as an independent risk factor for critical illness and major severity in subjects with coronavirus disease 2019 (COVID-19). The role of fat distribution, particularly visceral fat (often linked to metabolic abnormalities), is still unclear. The adipose tissue represents a direct source of cytokines responsible for the pathological modifications occurring within adipose tissue in obese subjects. Adipokines are a crucial connection between metabolism and immune system: their dysregulation in obesity contributes to chronic low-grade systemic inflammation and metabolic comorbidities. Therefore the increased amount of visceral fat can lead to a proinflammatory phenotypic shift. This review analyzes the interrelation between obesity and COVID-19 severity, as well as the cellular key players and molecular mechanisms implicated in adipose inflammation, investigating if adipose tissue can constitute a reservoir for viral spread, and contribute to immune activation and cytokines storm. Targeting the underlying molecular mechanisms might have therapeutic potential in the management of obesity-related complications in COVID-19 patients.

Gamma-oryzanol as a potential modulator of oxidative stress and inflammation via PPAR-y in adipose tissue: a hypothetical therapeutic for cytokine storm in COVID-19?

The literature has reported a higher prevalence of negative clinical outcomes due to Coronavirus disease 19 (COVID-19) in obese individuals. This can be explained by the cytokine storm, result from the cytokine production from both obesity and viral infection. Gamma-oryzanol (γOz) is a compound with anti-inflammatory and antioxidant activities. However, little is known about the γOz action as a possible agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). The aim of this study was to test the hypothesis that γOz attenuates the cytokine storm by stimulating PPAR-γ in the adipose tissue. METHODS: Male Wistar rats were randomly divided into three experimental groups and fed ad libitum for 30 weeks with control diet (C, n = 6), high sugar-fat diet (HSF, n = 6) or high sugar-fat diet + Î³Oz (HSF + Î³Oz, n = 6). HSF groups also received water + sucrose (25%). The γOz dose was 0.5% in the chow. Evaluation in animals included caloric intake, body weight, adiposity index, plasma triglycerides, and HOMA-IR. In adipose tissue was evaluated: PPAR-γ gene and protein expression, inflammatory and oxidative stress parameters, and histological analysis. RESULTS: Adipose tissue dysfunction was observed in HSF group, which presented remarkable PPAR-γ underexpression and increased levels of cytokines, other inflammatory markers and oxidative stress. The γOz treatment prevented adipose tissue dysfunction and promoted PPAR-γ overexpression. CONCLUSION: Natural compounds as γOz can be considered a coadjutant therapy to prevent the cytokine storm in COVID-19 patients with obesity conditions.

Epicardial adipose tissue, inflammatory biomarkers and COVID-19: Is there a possible relationship?

BACKGROUND & AIMS: Adipose tissue is a biologically active organ with pro-immunogenic properties. We aimed to evaluate the prognostic value of epicardial adipose tissue (EAT) in COVID-19 and its correlation with other inflammatory biomarkers. MATERIAL AND METHODS: One-hundred patients with COVID-19 were enrolled. C-reactive protein (CRP), lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-CRP ratio (LCR), and platelet-to-lymphocyte ratio (PLR) were evaluated on admission. EAT volume and density were measured by computed tomography. Patients were followed until death or discharge. Univariate and multivariate analysis was performed and ROC curve analysis was used to assess the ability of inflammatory markers in predicting survival. The relationship between EAT and other inflammatory markers was also investigated. RESULTS: The mean ± SD age of patients was 55.5 ± 15.2 years old; 68% were male. Univariate analysis revealed that increased lung involvement, blood urea nitrogen, LDH and NLR, and decreased platelet count were significantly associated with death. After adjustment, LDH was independently predictive of death (OR = 1.013, p-value = 0.03). Among inflammatory markers, LCR had the best ability for predicting survival with 79.7% sensitivity and 64.3% specificity at an optimal cut-off value of 20.8 (AUC = 0.744, 95% CI = 0.612-0.876, p-value = 0.004). EAT volume demonstrated positive correlation with NLR and PLR (p = 0.001 and 0.01), and a negative correlation with LCR (p = 0.02). EAT density was significantly different between decedents and survivors (p = 0.008). CONCLUSION: Routine laboratory tests that represent status of inflammation can be used as cost-effective prognostic markers of COVID-19. Also, the significant association between EAT volume and other inflammatory biomarkers might explain the more severe disease in obese patients.

Fat mass affects nutritional status of ICU COVID-19 patients.

BACKGROUND: Obesity and steatosis are associated with COVID-19 severe pneumonia. Elevated levels of pro-inflammatory cytokines and reduced immune response are typical of these patients. In particular, adipose tissue is the organ playing the crucial role. So, it is necessary to evaluate fat mass and not simpler body mass index (BMI), because BMI leaves a portion of the obese population unrecognized. The aim is to evaluate the relationship between Percentage of Fat Mass (FM%) and immune-inflammatory response, after 10 days in Intensive Care Unit (ICU). METHODS: Prospective observational study of 22 adult patients, affected by COVID-19 pneumonia and admitted to the ICU and classified in two sets: (10) lean and (12) obese, according to FM% and age (De Lorenzo classification). Patients were analyzed at admission in ICU and at 10th day. RESULTS: Obese have steatosis, impaired hepatic function, compromise immune response and higher inflammation. In addition, they have a reduced prognostic nutritional index (PNI), nutritional survival index for ICU patients. CONCLUSION: This is the first study evaluating FM% in COVID-19 patient. We underlined obese characteristic with likely poorly prognosis and an important misclassification of obesity. A not negligible number of patients with normal BMI could actually have an excess of adipose tissue and therefore have an unfavorable outcome such as an obese. Is fundamental personalized patients nutrition basing on disease phases.