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1.
Metabolism ; 133: 155236, 2022 08.
Article in English | MEDLINE | ID: covidwho-2131881

ABSTRACT

BACKGROUND: COVID-19 can cause multiple organ damages as well as metabolic abnormalities such as hyperglycemia, insulin resistance, and new onset of diabetes. The insulin/IGF signaling pathway plays an important role in regulating energy metabolism and cell survival, but little is known about the impact of SARS-CoV-2 infection. The aim of this work was to investigate whether SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the host cell/tissue, and if so, the potential mechanism and association with COVID-19 pathology. METHODS: To determine the impact of SARS-CoV-2 on insulin/IGF signaling pathway, we utilized transcriptome datasets of SARS-CoV-2 infected cells and tissues from public repositories for a wide range of high-throughput gene expression data: autopsy lungs from COVID-19 patients compared to the control from non-COVID-19 patients; lungs from a human ACE2 transgenic mouse infected with SARS-CoV-2 compared to the control infected with mock; human pluripotent stem cell (hPSC)-derived liver organoids infected with SARS-CoV-2; adipose tissues from a mouse model of COVID-19 overexpressing human ACE2 via adeno-associated virus serotype 9 (AAV9) compared to the control GFP after SARS-CoV-2 infection; iPS-derived human pancreatic cells infected with SARS-CoV-2 compared to the mock control. Gain and loss of IRF1 function models were established in HEK293T and/or Calu3 cells to evaluate the impact on insulin signaling. To understand the mechanistic regulation and relevance with COVID-19 risk factors, such as older age, male sex, obesity, and diabetes, several transcriptomes of human respiratory, metabolic, and endocrine cells and tissue were analyzed. To estimate the association with COVID-19 severity, whole blood transcriptomes of critical patients with COVID-19 compared to those of hospitalized noncritical patients with COVID-19. RESULTS: We found that SARS-CoV-2 infection impaired insulin/IGF signaling pathway genes, such as IRS, PI3K, AKT, mTOR, and MAPK, in the host lung, liver, adipose tissue, and pancreatic cells. The impairments were attributed to interferon regulatory factor 1 (IRF1), and its gene expression was highly relevant to risk factors for severe COVID-19; increased with aging in the lung, specifically in men; augmented by obese and diabetic conditions in liver, adipose tissue, and pancreatic islets. IRF1 activation was significantly associated with the impaired insulin signaling in human cells. IRF1 intron variant rs17622656-A, which was previously reported to be associated with COVID-19 prevalence, increased the IRF1 gene expression in human tissue and was frequently found in American and European population. Critical patients with COVID-19 exhibited higher IRF1 and lower insulin/IGF signaling pathway genes in the whole blood compared to hospitalized noncritical patients. Hormonal interventions, such as dihydrotestosterone and dexamethasone, ameliorated the pathological traits in SARS-CoV-2 infectable cells and tissues. CONCLUSIONS: The present study provides the first scientific evidence that SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in respiratory, metabolic, and endocrine cells and tissues. This feature likely contributes to COVID-19 severity with cell/tissue damage and metabolic abnormalities, which may be exacerbated in older, male, obese, or diabetic patients.


Subject(s)
COVID-19 , Insulin , Interferon Regulatory Factor-1 , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , HEK293 Cells , Humans , Insulin/metabolism , Interferon Regulatory Factor-1/metabolism , Male , Mice , Mice, Transgenic , Obesity/metabolism , Obesity/pathology , SARS-CoV-2 , Signal Transduction
2.
Int J Mol Sci ; 23(19)2022 Oct 07.
Article in English | MEDLINE | ID: covidwho-2066142

ABSTRACT

The role of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in the regulation of energy homeostasis remains poorly understood. In this study, we used a transgenic fat-1 mouse model, which can produce n-3 PUFAs endogenously, to investigate how n-3 PUFAs regulate the morphology and function of brown adipose tissue (BAT). We found that high-fat diet (HFD) induced a remarkable morphological change in BAT, characterized by "whitening" due to large lipid droplet accumulation within BAT cells, associated with obesity in wild-type (WT) mice, whereas the changes in body fat mass and BAT morphology were significantly alleviated in fat-1 mice. The expression of thermogenic markers and lypolytic enzymes was significantly higher in fat-1 mice than that in WT mice fed with HFD. In addition, fat-1 mice had significantly lower levels of inflammatory markers in BAT and lipopolysaccharide (LPS) in plasma compared with WT mice. Furthermore, fat-1 mice were resistant to LPS-induced suppression of UCP1 and PGC-1 expression and lipid deposits in BAT. Our data has demonstrated that high-fat diet-induced obesity is associated with impairments of BAT morphology (whitening) and function, which can be ameliorated by elevated tissue status of n-3 PUFAs, possibly through suppressing the effects of LPS on inflammation and thermogenesis.


Subject(s)
Adipose Tissue, Brown , Fatty Acids, Omega-3 , Adipose Tissue, Brown/metabolism , Animals , Diet, High-Fat/adverse effects , Fatty Acids, Omega-3/metabolism , Fatty Acids, Omega-3/pharmacology , Fatty Acids, Unsaturated/metabolism , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Obesity/genetics , Obesity/metabolism , Thermogenesis
3.
Front Immunol ; 13: 943333, 2022.
Article in English | MEDLINE | ID: covidwho-2022722

ABSTRACT

Mesenchymal stromal cell (MSC) therapy has seen increased attention as a possible option to treat a number of inflammatory conditions including COVID-19 acute respiratory distress syndrome (ARDS). As rates of obesity and metabolic disease continue to rise worldwide, increasing proportions of patients treated with MSC therapy will be living with obesity. The obese environment poses critical challenges for immunomodulatory therapies that should be accounted for during development and testing of MSCs. In this review, we look to cancer immunotherapy as a model for the challenges MSCs may face in obese environments. We then outline current evidence that obesity alters MSC immunomodulatory function, drastically modifies the host immune system, and therefore reshapes interactions between MSCs and immune cells. Finally, we argue that obese environments may alter essential features of allogeneic MSCs and offer potential strategies for licensing of MSCs to enhance their efficacy in the obese microenvironment. Our aim is to combine insights from basic research in MSC biology and clinical trials to inform new strategies to ensure MSC therapy is effective for a broad range of patients.


Subject(s)
COVID-19 , Mesenchymal Stem Cells , COVID-19/therapy , Cells, Cultured , Humans , Immunomodulation , Mesenchymal Stem Cells/metabolism , Obesity/metabolism , Obesity/therapy
4.
J Immunol ; 209(7): 1323-1334, 2022 10 01.
Article in English | MEDLINE | ID: covidwho-2002569

ABSTRACT

Obesity is considered an important comorbidity for a range of noninfectious and infectious disease states including those that originate in the lung, yet the mechanisms that contribute to this susceptibility are not well defined. In this study, we used the diet-induced obesity (DIO) mouse model and two models of acute pulmonary infection, Francisella tularensis subspecies tularensis strain SchuS4 and SARS-CoV-2, to uncover the contribution of obesity in bacterial and viral disease. Whereas DIO mice were more resistant to infection with SchuS4, DIO animals were more susceptible to SARS-CoV-2 infection compared with regular weight mice. In both models, neither survival nor morbidity correlated with differences in pathogen load, overall cellularity, or influx of inflammatory cells in target organs of DIO and regular weight animals. Increased susceptibility was also not associated with exacerbated production of cytokines and chemokines in either model. Rather, we observed pathogen-specific dysregulation of the host lipidome that was associated with vulnerability to infection. Inhibition of specific pathways required for generation of lipid mediators reversed resistance to both bacterial and viral infection. Taken together, our data demonstrate disparity among obese individuals for control of lethal bacterial and viral infection and suggest that dysregulation of the host lipidome contributes to increased susceptibility to viral infection in the obese host.


Subject(s)
COVID-19 , Francisella tularensis , Tularemia , Virus Diseases , Animals , Chemokines/metabolism , Cytokines/metabolism , Lipids , Lung/microbiology , Mice , Mice, Inbred C57BL , Obesity/metabolism , SARS-CoV-2 , Virus Diseases/metabolism
5.
J Nutr Biochem ; 108: 109092, 2022 10.
Article in English | MEDLINE | ID: covidwho-1983513

ABSTRACT

Both obesity and cancer are complex medical conditions that are considered public health problems. The influence of obesity on the predisposition to develop various types of cancer has been observed in a wide variety of studies. Due to their importance as public health problems, and the close relationship between both conditions, it is important to be able to understand and associate them mechanistically. In this review article, we intend to go a little further, by finding relationships between lifestyle, which can lead a person to develop obesity, and how it influences at the cellular and molecular level, affecting gene expression to favor signaling pathways or transcriptional programs involved in cancer. We describe how products of metabolism and intermediate metabolism can affect chromatin structure, participating in the regulation (or dysregulation) of gene expression, and we show an analysis of genes that are responsive to diets high in sugar and fat, and how their epigenetic landscape is altered.


Subject(s)
Epigenesis, Genetic , Pandemics , Carcinogenesis/genetics , Diet/adverse effects , Humans , Obesity/metabolism
7.
Cells ; 11(13)2022 07 04.
Article in English | MEDLINE | ID: covidwho-1917305

ABSTRACT

In the last 30 years the adipose cell has been object of several studies, turning its reputation from an inert cell into the main character involved in the pathophysiology of multiple diseases, including the ongoing COVID-19 pandemic, which has changed the clinical scenario of the last two years. Composed by two types of tissue (white and brown), with opposite roles, the adipose organ is now classified as a real endocrine organ whose dysfunction is involved in different diseases, mainly obesity and type 2 diabetes. In this mini-review we aim to retrace the adipose organ history from physiology to physiopathology, to provide therapeutic perspectives for the prevention and treatment of its two main related diseases (obesity and type 2 diabetes) and to summarize the most recent discoveries linking adipose tissue to COVID-19.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Adipose Tissue, Brown/metabolism , Diabetes Mellitus, Type 2/metabolism , Humans , Obesity/metabolism , Pandemics
8.
Cells ; 11(6)2022 03 14.
Article in English | MEDLINE | ID: covidwho-1887165

ABSTRACT

The epicardial adipose tissue (EAT) is the visceral fat depot of the heart which is highly plastic and in direct contact with myocardium and coronary arteries. Because of its singular proximity with the myocardium, the adipokines and pro-inflammatory molecules secreted by this tissue may directly affect the metabolism of the heart and coronary arteries. Its accumulation, measured by recent new non-invasive imaging modalities, has been prospectively associated with the onset and progression of coronary artery disease (CAD) and atrial fibrillation in humans. Recent studies have shown that EAT exhibits beige fat-like features, and express uncoupling protein 1 (UCP-1) at both mRNA and protein levels. However, this thermogenic potential could be lost with age, obesity and CAD. Here we provide an overview of the physiological and pathophysiological relevance of EAT and further discuss whether its thermogenic properties may serve as a target for obesity therapeutic management with a specific focus on the role of immune cells in this beiging phenomenon.


Subject(s)
Adipose Tissue , Coronary Artery Disease , Adipokines/metabolism , Adipose Tissue/metabolism , Coronary Artery Disease/metabolism , Humans , Obesity/metabolism , Pericardium/metabolism
9.
Int J Mol Sci ; 23(9)2022 Apr 28.
Article in English | MEDLINE | ID: covidwho-1847341

ABSTRACT

Obesity is a leading cause of preventable death and morbidity. To elucidate the mechanisms connecting metabolically active brown adipose tissue (BAT) and metabolic health may provide insights into methods of treatment for obesity-related conditions. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) is traditionally used to image human BAT activity. However, the primary energy source of BAT is derived from intracellular fatty acids and not glucose. Beta-methyl-p-iodophenylpentadecanoic acid (BMIPP) is a fatty acid analogue amenable to in vivo imaging by single photon emission computed tomography/CT (SPECT/CT) when radiolabeled with iodine isotopes. In this study, we compare the use of 18FDG-PET/CT and 125I-BMIPP-SPECT/CT for fat imaging to ascertain whether BMIPP is a more robust candidate for the non-invasive evaluation of metabolically active adipose depots. Interscapular BAT, inguinal white adipose tissue (iWAT), and gonadal white adipose tissue (gWAT) uptake of 18FDG and 125I-BMIPP was quantified in mice following treatment with the BAT-stimulating drug CL-316,243 or saline vehicle control. After CL-316,243 treatment, uptake of both radiotracers increased in BAT and iWAT. The standard uptake value (SUVmean) for 18FDG and 125I-BMIPP significantly correlated in these depots, although uptake of 125I-BMIPP in BAT and iWAT more closely mimicked the fold-change in metabolic rate as measured by an extracellular flux analyzer. Herein, we find that imaging BAT with the radioiodinated fatty acid analogue BMIPP yields more physiologically relevant data than 18FDG-PET/CT, and its conventional use may be a pivotal tool for evaluating BAT in both mice and humans.


Subject(s)
Adipose Tissue, Brown , Fluorodeoxyglucose F18 , Adipose Tissue, Brown/diagnostic imaging , Adipose Tissue, Brown/metabolism , Animals , Fatty Acids/metabolism , Fluorodeoxyglucose F18/metabolism , Iodobenzenes , Mice , Obesity/metabolism , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Radiopharmaceuticals/metabolism , Tomography, Emission-Computed, Single-Photon/methods
10.
Nat Rev Nephrol ; 17(11): 725-739, 2021 11.
Article in English | MEDLINE | ID: covidwho-1821594

ABSTRACT

Obesity, diabetes mellitus, hypertension and cardiovascular disease are risk factors for chronic kidney disease (CKD) and kidney failure. Chronic, low-grade inflammation is recognized as a major pathogenic mechanism that underlies the association between CKD and obesity, impaired glucose tolerance, insulin resistance and diabetes, through interaction between resident and/or circulating immune cells with parenchymal cells. Thus, considerable interest exists in approaches that target inflammation as a strategy to manage CKD. The initial phase of the inflammatory response to injury or metabolic dysfunction reflects the release of pro-inflammatory mediators including peptides, lipids and cytokines, and the recruitment of leukocytes. In self-limiting inflammation, the evolving inflammatory response is coupled to distinct processes that promote the resolution of inflammation and restore homeostasis. The discovery of endogenously generated lipid mediators - specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids - which promote the resolution of inflammation and attenuate the microvascular and macrovascular complications of obesity and diabetes mellitus highlights novel opportunities for potential therapeutic intervention through the targeting of pro-resolution, rather than anti-inflammatory pathways.


Subject(s)
Diabetic Nephropathies/metabolism , Inflammation Mediators/metabolism , Inflammation/metabolism , Kidney/metabolism , Lipid Metabolism , Lipids , Renal Insufficiency, Chronic/metabolism , Diabetes Mellitus/metabolism , Diabetic Angiopathies/metabolism , Humans , Obesity/metabolism
11.
Cytokine ; 153: 155868, 2022 05.
Article in English | MEDLINE | ID: covidwho-1763681

ABSTRACT

The COVID-19 disease has forced us to consider the physiologic role of obesity and metabolically healthy and unhealthy status in response to SARS-CoV-2 infection. Hematological, coagulation, biochemical, and immunoinflammatory changes have been informed with a disparity in morbidity and mortality. Therefore, we aimed to investigate the influence of metabolic health on clinical features in a cross-sectional study in Mexican subjects with and without SARS-CoV-2 infection in non-severe stages after a rigorous classification of obese and non-obese subjects who were metabolically healthy and unhealthy. Four groups were formed: 1) metabolically healthy with normal BMI (MHN); 2) metabolically unhealthy with normal BMI (MUN); 3) metabolically healthy obese (MHO); 4) metabolically unhealthy obese (MUO). Serum proinflammatory (TNF-α, MCP-1, IL-1ß, and IL-6) and anti-inflammatory (TGF-ß, IL-1Ra, IL-4, and IL-10) cytokines, hematological parameters, coagulation, and acute phase components were evaluated. Our results showed that MHO people live with inflammaging. Meanwhile, MUN and MUO subjects develop metaflammation. Both inflammaging and metaflammation cause imperceptible modifications on hematological parameters, mainly in leukocyte populations and platelets, as well as acute phase and coagulation components. The statistical analysis revealed that many clinical features are dependent on metabolic health. In conclusion, MHO subjects seem to be transitioning from metabolically healthy to unhealthy, which is accelerated in acute processes, such as SARS-CoV-2 infection. Meanwhile, metabolically unhealthy subjects independently of BMI have a deteriorating immunometabolic status associated with a hyperinflammatory state leading to multi-organ dysfunction, treatment complications, and severe COVID-19 disease.


Subject(s)
COVID-19 , Metabolic Syndrome , Body Mass Index , Cross-Sectional Studies , Humans , Obesity/metabolism , Risk Factors , SARS-CoV-2
12.
Int J Mol Sci ; 23(5)2022 Feb 23.
Article in English | MEDLINE | ID: covidwho-1715405

ABSTRACT

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)-a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer-particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glutathione/analogs & derivatives , Hesperidin/therapeutic use , Lactoylglutathione Lyase/metabolism , Neoplasms, Experimental/drug therapy , Resveratrol/therapeutic use , Animals , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Drug Therapy, Combination , Enzyme Induction/drug effects , Glutathione/chemistry , Glutathione/therapeutic use , Glycosylation/drug effects , Hesperidin/chemistry , Humans , Insulin Resistance/physiology , Lactoylglutathione Lyase/antagonists & inhibitors , Mice , Molecular Structure , Neoplasms, Experimental/metabolism , Obesity/drug therapy , Obesity/metabolism , Obesity/physiopathology , Pyruvaldehyde/chemistry , Pyruvaldehyde/metabolism , Resveratrol/chemistry
13.
Int J Mol Sci ; 23(4)2022 Feb 19.
Article in English | MEDLINE | ID: covidwho-1715401

ABSTRACT

Obesity is an increasingly severe public health problem, which brings huge social and economic burdens. Increased body adiposity in obesity is not only tightly associated with type 2 diabetes, but also significantly increases the risks of other chronic diseases including cardiovascular diseases, fatty liver diseases and cancers. Adipogenesis describes the process of the differentiation and maturation of adipocytes, which accumulate in distributed adipose tissue at various sites in the body. The major functions of white adipocytes are to store energy as fat during periods when energy intake exceeds expenditure and to mobilize this stored fuel when energy expenditure exceeds intake. Brown/beige adipocytes contribute to non-shivering thermogenesis upon cold exposure and adrenergic stimulation, and thereby promote energy consumption. The imbalance of energy intake and expenditure causes obesity. Recent interest in epigenetics and signaling pathways has utilized small molecule tools aimed at modifying obesity-specific gene expression. In this review, we discuss compounds with adipogenesis-related signaling pathways and epigenetic modulating properties that have been identified as potential therapeutic agents which cast some light on the future treatment of obesity.


Subject(s)
Adipogenesis/drug effects , Anti-Obesity Agents/pharmacology , Obesity/drug therapy , Adiposity/drug effects , Animals , Energy Metabolism/drug effects , Humans , Obesity/metabolism , Signal Transduction/drug effects , Thermogenesis/drug effects
15.
Biomolecules ; 12(2)2022 01 31.
Article in English | MEDLINE | ID: covidwho-1677658

ABSTRACT

Amino acid transporters are expressed in mammalian cells not only in the plasma membrane but also in intracellular membranes. The conventional function of these transporters is to transfer their amino acid substrates across the lipid bilayer; the direction of the transfer is dictated by the combined gradients for the amino acid substrates and the co-transported ions (Na+, H+, K+ or Cl-) across the membrane. In cases of electrogenic transporters, the membrane potential also contributes to the direction of the amino acid transfer. In addition to this expected traditional function, several unconventional functions are known for some of these amino acid transporters. This includes their role in intracellular signaling, regulation of acid-base balance, and entry of viruses into cells. Such functions expand the biological roles of these transporters beyond the logical amino acid homeostasis. In recent years, two additional unconventional biochemical/metabolic processes regulated by certain amino acid transporters have come to be recognized: macropinocytosis and obesity. This adds to the repertoire of biological processes that are controlled and regulated by amino acid transporters in health and disease. In the present review, we highlight the unusual involvement of selective amino acid transporters in macropinocytosis (SLC38A5/SLC38A3) and diet-induced obesity/metabolic syndrome (SLC6A19/SLC6A14/SLC6A6).


Subject(s)
Metabolic Syndrome , Amino Acid Transport Systems/metabolism , Animals , Biological Transport , Diet , Mammals/metabolism , Obesity/metabolism
16.
Nutrients ; 14(3)2022 Jan 30.
Article in English | MEDLINE | ID: covidwho-1667257

ABSTRACT

Obesity is characterized by low-grade inflammation and more susceptibility to infection, particularly viral infections, as clearly demonstrated in COVID-19. In this context, immunometabolism and metabolic flexibility of macrophages play an important role. Since inflammation is an inherent part of the innate response, strategies for decreasing the inflammatory response must avoid immunocompromise the innate defenses against pathogen challenges. The concept "bioregulation of inflammatory/innate responses" was coined in the context of the effects of exercise on these responses, implying a reduction in excessive inflammatory response, together with the preservation or stimulation of the innate response, with good transitions between pro- and anti-inflammatory macrophages adapted to each individual's inflammatory set-point in inflammatory diseases, particularly in obesity. The question now is whether these responses can be obtained in the context of weight loss by dietary interventions (low-fat diet or abandonment of the high-fat diet) in the absence of exercise, which can be especially relevant for obese individuals with difficulties exercising such as those suffering from persistent COVID-19. Results from recent studies are controversial and do not point to a clear anti-inflammatory effect of these dietary interventions, particularly in the adipose tissue. Further research focusing on the innate response is also necessary.


Subject(s)
COVID-19 , Humans , Inflammation/metabolism , Macrophages/metabolism , Obesity/metabolism , SARS-CoV-2 , Weight Loss
17.
Int J Obes (Lond) ; 46(5): 1009-1017, 2022 05.
Article in English | MEDLINE | ID: covidwho-1655531

ABSTRACT

BACKGROUND: Preliminary data suggested that fat embolism could explain the importance of visceral obesity as a critical determinant of coronavirus disease-2019 (COVID-19). METHODS: We performed a comprehensive histomorphologic analysis of autoptic visceral adipose tissue (VAT), lungs and livers of 19 subjects with COVID-19 (COVID-19+), and 23 people without COVID-19 (controls). Human adipocytes (hMADS) infected with SARS-CoV-2 were also studied. RESULTS: Although there were no between-group differences in body-mass-index and adipocytes size, a higher prevalence of CD68+ macrophages among COVID-19+ VAT was detected (p = 0.005) and accompanied by crown-like structures presence, signs of adipocytes stress and death. Consistently, human adipocytes were successfully infected by SARS-CoV-2 in vitro and displayed lower cell viability. Being VAT inflammation associated with lipids spill-over from dead adipocytes, we studied lipids distribution by ORO. Lipids were observed within lungs and livers interstitial spaces, macrophages, endothelial cells, and vessels lumen, features suggestive of fat embolism syndrome, more prevalent among COVID-19+ (p < 0.001). Notably, signs of fat embolism were more prevalent among people with obesity (p = 0.03) independently of COVID-19 diagnosis, suggesting that such condition may be an obesity complication exacerbated by SARS-CoV-2 infection. Importantly, all infected subjects' lungs presented lipids-rich (ORO+) hyaline membranes, formations associated with COVID-19-related pneumonia, present only in one control patient with non-COVID-19-related pneumonia. Importantly, transition aspects between embolic fat and hyaline membranes were also observed. CONCLUSIONS: This study confirms the lung fat embolism in COVID-19+ patients and describes for the first time novel COVID-19-related features possibly underlying the unfavorable prognosis in people with COVID-19 and obesity.


Subject(s)
COVID-19 , Embolism, Fat , COVID-19/complications , COVID-19 Testing , Endothelial Cells/metabolism , Humans , Hyalin/metabolism , Inflammation/metabolism , Intra-Abdominal Fat/metabolism , Lipids , Lung , Obesity/metabolism , SARS-CoV-2
18.
Bull Exp Biol Med ; 172(3): 283-287, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1611428

ABSTRACT

We studied laboratory parameters of patients with COVID-19 against the background of chronic pathologies (cardiovascular pathologies, obesity, type 2 diabetes melitus, and cardiovascular pathologies with allergy to statins). A decrease in pH and a shift in the electrolyte balance of blood plasma were revealed in all studied groups and were most pronounced in patients with cardiovascular pathologies with allergy to statin. It was found that low pH promotes destruction of lipid components of the erythrocyte membranes in patients with chronic pathologies, which was seen from a decrease in Na+/K+-ATPase activity and significant hyponatrenemia. In patients with cardiovascular pathologies and allergy to statins, erythrocyte membranes were most sensitive to a decrease in pH, while erythrocyte membranes of obese patients showed the greatest resistance to low pH and oxidative stress.


Subject(s)
COVID-19/complications , Hyponatremia/etiology , Hypoxia/complications , Sodium-Potassium-Exchanging ATPase/physiology , Aged , COVID-19/metabolism , Cardiovascular Diseases/complications , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/virology , Case-Control Studies , Chronic Disease , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/virology , Drug Hypersensitivity/complications , Drug Hypersensitivity/metabolism , Drug Hypersensitivity/virology , Erythrocyte Membrane/metabolism , Erythrocytes/metabolism , Female , Fluid Shifts/physiology , Humans , Hydrogen-Ion Concentration , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hyponatremia/metabolism , Hyponatremia/virology , Hypoxia/metabolism , Lipid Peroxidation/physiology , Male , Middle Aged , Obesity/complications , Obesity/metabolism , Obesity/virology , Oxidative Stress/physiology , SARS-CoV-2/physiology , Sodium/metabolism , Stress, Physiological/physiology
19.
Obes Rev ; 23(5): e13415, 2022 05.
Article in English | MEDLINE | ID: covidwho-1604448

ABSTRACT

Type 2 diabetes (T2D) and obesity are independent risk factors for increased morbidity and mortality associated with influenza and SARS-CoV-2 infection. Skewed cellular metabolism shapes immune cell inflammatory responsiveness and function in obesity, T2D, and infection. However, altered immune cell responsiveness and levels of systemic proinflammatory mediators, partly independent of peripheral immune cell contribution, are linked with SARS-CoV-2-associated disease severity. Despite such knowledge, the role of tissue parenchymal cell-driven inflammatory responses, and specifically those dominantly modified in obesity (e.g., adipocytes), in influenza and SARS-CoV-2 infection pathogenesis remain poorly defined. Whether obesity-dependent skewing of adipocyte cellular metabolism uncovers inflammatory clades and promotes the existence of a 'pathogenic-inflammatory' adipocyte phenotype that amplifies SARS-CoV-2 infection diseases severity in individuals with obesity and individuals with obesity and T2D has not been examined. Here, using the knowledge gained from studies of immune cell responses in obesity, T2D, and infection, we highlight the key knowledge gaps underlying adipocyte cellular functions that may sculpt and grease pathogenic processes associated with influenza and SARS-CoV-2 disease severity in diabetes.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Influenza, Human , Pneumonia, Viral , Diabetes Mellitus, Type 2/etiology , Humans , Influenza, Human/complications , Influenza, Human/pathology , Obesity/metabolism , Pneumonia, Viral/complications , SARS-CoV-2
20.
Biochem Soc Trans ; 50(1): 447-457, 2022 02 28.
Article in English | MEDLINE | ID: covidwho-1599610

ABSTRACT

Obesity and its associated metabolic diseases, including diabetes, insulin resistance, and inflammation, are rapidly becoming a global health concern. Moreover, obese individuals are more likely to be infected with COVID-19. New research on adipose tissue is required to help us understand these metabolic diseases and their regulatory processes. Recently, extracellular vesicles (EVs) have been identified as novel intercellular vectors with a wide range of regulatory functions. The miRNAs carried by EVs participate in the regulation of white adipose tissue (WAT) browning, insulin resistance, diabetes, and inflammation. In addition, EV miRNAs demonstrate great potential for helping elucidating the mechanism of metabolic diseases, and for advancing their prevention and treatment. In this review, we focus on the mechanisms underlying the regulation of adipose differentiation and metabolic diseases by adipose-derived EV miRNAs. Understanding the role of these miRNAs should enrich our understanding of the etiology and pathogenesis of metabolic diseases caused by obesity.


Subject(s)
Adipose Tissue/metabolism , Extracellular Vesicles/metabolism , MicroRNAs , Obesity/metabolism , Animals , Humans
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