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1.
Int J Mol Sci ; 22(18)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34575910

RESUMO

The susceptibility and the severity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with hyperandrogenism, obesity, and preexisting pulmonary, metabolic, renal, and cardiac conditions. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with obesity, hyperandrogenism, and cardiometabolic dysregulations. We analyzed cardiac, renal, circulatory, and urinary SARS-CoV-2 viral entry proteins (ACE2, TMPRSS2, TMPRSS4, furin, cathepsin L, and ADAM17) and androgen receptor (AR) expression, in a peripubertal androgen exposure model of PCOS. Peripubertal female mice were treated with dihydrotestosterone (DHT) and low (LFD) or high (HFD) fat diet for 90 days. HFD exacerbated DHT-induced increase in body weight, fat mass, and cardiac and renal hypertrophy. In the heart, DHT upregulated AR protein in both LFD and HFD, ACE2 in HFD, and ADAM17 in LFD. In the kidney, AR protein expression was upregulated by both DHT and HFD. Moreover, ACE2 and ADAM17 were upregulated by DHT in both diets. Renal TMPRSS2, furin, and cathepsin L were upregulated by DHT and differentially modulated by the diet. DHT upregulated urinary ACE2 in both diets, while neither treatment modified serum ACE2. Renal AR mRNA expression positively correlated with Ace2, Tmprss2, furin, cathepsin L, and ADAM17. Our findings suggest that women with PCOS could be a population with a high risk of COVID-19-associated cardiac and renal complications. Furthermore, our study suggests that weight loss by lifestyle modifications (i.e., diet) could potentially mitigate COVID-19-associated deleterious cardiorenal outcomes in women with PCOS.


Assuntos
COVID-19 , Obesidade , Síndrome do Ovário Policístico/virologia , Receptores de Coronavírus/imunologia , SARS-CoV-2/fisiologia , Internalização do Vírus , Animais , COVID-19/imunologia , COVID-19/virologia , Feminino , Coração , Rim , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/imunologia , Obesidade/virologia
2.
Front Immunol ; 12: 739025, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531877

RESUMO

A rise in adiposity in the United States has resulted in more than 70% of adults being overweight or obese, and global obesity rates have tripled since 1975. Following the 2009 H1N1 pandemic, obesity was characterized as a risk factor that could predict severe infection outcomes to viral infection. Amidst the SARS-CoV-2 pandemic, obesity has remained a significant risk factor for severe viral disease as obese patients have a higher likelihood for developing severe symptoms and requiring hospitalization. However, the mechanism by which obesity enhances viral disease is unknown. In this study, we utilized a diet-induced obesity mouse model of West Nile virus (WNV) infection, a flavivirus that cycles between birds and mosquitoes and incidentally infects both humans and mice. Likelihood for severe WNV disease is associated with risk factors such as diabetes that are comorbidities also linked to obesity. Utilizing this model, we showed that obesity-associated chronic inflammation increased viral disease severity as obese female mice displayed higher mortality rates and elevated viral titers in the central nervous system. In addition, our studies highlighted that obesity also dysregulates host acute adaptive immune responses, as obese female mice displayed significant dysfunction in neutralizing antibody function. These studies highlight that obesity-induced immunological dysfunction begins at early time points post infection and is sustained through memory phase, thus illuminating a potential for obesity to alter the differentiation landscape of adaptive immune cells.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Citocinas/sangue , Obesidade/imunologia , Febre do Nilo Ocidental/mortalidade , Vírus do Nilo Ocidental/imunologia , Animais , COVID-19/patologia , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/patologia , Fígado/lesões , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/patologia , Índice de Gravidade de Doença , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/patologia
3.
Eur J Endocrinol ; 184(6): 857-865, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34552304

RESUMO

Objective: Obese and overweight body mass index (BMI) categories have been associated with increased immune-related adverse events (irAEs) in patients with cancer receiving immune checkpoint inhibitors (ICIs); however, the impact of being overweight in conjunction with related metabolic syndrome-associated factors on irAEs have not been investigated. We aimed to evaluate the impact of overweight and obese BMI according to metabolic disease burden on the development of irAEs. Design and Methods: We conducted a retrospective observational study of patients receiving ICIs at a cancer center. Our main study outcome was development of ≥grade 2 (moderate) irAEs. Our main predictor was weight/metabolic disease risk category: (1) normal weight (BMI 18.5-24.9 kg/m2)/low metabolic risk (<2 metabolic diseases [diabetes, dyslipidemia, hypertension]), (2) normal weight/high metabolic risk (≥2 metabolic diseases), (3) overweight (BMI ≥25 kg/m2)/low metabolic risk, and (4) overweight/high metabolic risk. Results: Of 411 patients in our cohort, 374 were eligible for analysis. Overall, 111 (30%) patients developed ≥grade 2 irAEs. In Cox analysis, overweight/low metabolic risk was significantly associated with ≥grade 2 irAEs (hazard ratio [HR]: 2.0, 95% confidence interval [95% CI]: 1.2-3.4) when compared to normal weight/low metabolic risk, while overweight/high metabolic risk (HR: 1.3, 95% CI: 0.7-2.2) and normal weight/high metabolic risk (HR: 1.5, 95% CI: 0.7-3.0) were not. Conclusions: Overweight patients with fewer metabolic comorbidities were at increased risk for irAEs. This study provides an important insight that BMI should be evaluated in the context of associated metabolic comorbidities in assessing risk of irAE development and ICI immune response.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Doenças Metabólicas/epidemiologia , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Coortes , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Seguimentos , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/imunologia , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/imunologia , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/imunologia , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/imunologia , Sobrepeso/complicações , Sobrepeso/epidemiologia , Sobrepeso/imunologia , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Adulto Jovem
4.
Front Endocrinol (Lausanne) ; 12: 726967, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484128

RESUMO

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.


Assuntos
COVID-19/metabolismo , Cardiomiopatias/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/complicações , COVID-19/imunologia , Cardiomiopatias/imunologia , Cardiomiopatias/patologia , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Inflamação , Gordura Intra-Abdominal/patologia , Obesidade/complicações , Obesidade/imunologia , Obesidade/patologia , Pericárdio , Prognóstico , SARS-CoV-2/metabolismo , Serina Endopeptidases/metabolismo
5.
Nat Immunol ; 22(9): 1175-1185, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34429546

RESUMO

Systematic characterizations of adipose regulatory T (Treg) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose Treg cells, we identified CD73hiST2lo and CD73loST2hi subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73hiST2lo and CD73loST2hi subsets. Mechanistically, we revealed that insulin signaling occurs through a HIF-1α-Med23-PPAR-γ axis to drive the transition of CD73hiST2lo into a CD73loST2hi adipose Treg cell subset. Treg cells deficient in insulin receptor, HIF-1α or Med23 have decreased PPAR-γ expression that in turn promotes accumulation of CD73hiST2lo adipose Treg cells and physiological adenosine production to activate beige fat biogenesis. We therefore unveiled a developmental trajectory of adipose Treg cells and its dependence on insulin signaling. Our findings have implications for understanding the dynamics of adipose Treg cell subsets in aged and obese contexts.


Assuntos
Tecido Adiposo/imunologia , Resistência à Insulina/imunologia , Insulina/metabolismo , Receptor de Insulina/metabolismo , Linfócitos T Reguladores/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Tecido Adiposo/citologia , Envelhecimento/imunologia , Animais , Células Cultivadas , Sequenciamento de Nucleotídeos em Larga Escala , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Masculino , Complexo Mediador/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/imunologia , PPAR gama/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/citologia
6.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445503

RESUMO

Obesity is a major risk factor for developing cancer, with obesity-induced immune changes and inflammation in breast (BC) and colorectal cancer (CRC) providing a potential link between the two. This study investigates systemic effects of obesity on adaptive and innate immune cells in healthy and tumour-bearing mice. Immune cells from lean and obese mice were phenotyped prior to implantation of either BC (C57mg and EO771.LMB) or CRC (MC38) cells as tumour models. Tumour growth rate, tumour-infiltrating lymphocytes (TIL) and peripheral blood immune cell populations were compared between obese and lean mice. In vitro studies showed that naïve obese mice had higher levels of myeloid cells in the bone marrow and bone marrow-derived dendritic cells expressed lower levels of activation markers compared to cells from their lean counterparts. In the tumour setting, BC tumours grew faster in obese mice than in lean mice and lower numbers of TILs as well as higher frequency of exhausted T cells were observed. Data from peripheral blood showed lower levels of myeloid cells in tumour-bearing obese mice. This study highlights that systemic changes to the immune system are relevant for tumour burden and provides a potential mechanism behind the effects of obesity on cancer development and progression in patients.


Assuntos
Neoplasias da Mama/patologia , Neoplasias Colorretais/patologia , Linfócitos do Interstício Tumoral/metabolismo , Obesidade/imunologia , Imunidade Adaptativa , Animais , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Feminino , Humanos , Masculino , Camundongos , Células Mieloides/metabolismo , Transplante de Neoplasias , Microambiente Tumoral
7.
Biosci Rep ; 41(8)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34350941

RESUMO

An influenza-like virus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19 disease and spread worldwide within a short time. COVID-19 has now become a significant concern for public health. Obesity is highly prevalent worldwide and is considered a risk factor for impairing the adaptive immune system. Although diabetes, hypertension, cardiovascular disease (CVD), and renal failure are considered the risk factors for COVID-19, obesity is not yet well-considered. The present study approaches establishing a systemic association between the prevalence of obesity and its impact on immunity concerning the severe outcomes of COVID-19 utilizing existing knowledge. Overall study outcomes documented the worldwide prevalence of obesity, its effects on immunity, and a possible underlying mechanism covering obesity-related risk pathways for the severe outcomes of COVID-19. Overall understanding from the present study is that being an immune system impairing factor, the role of obesity in the severe outcomes of COVID-19 is worthy.


Assuntos
Imunidade Adaptativa/imunologia , COVID-19/patologia , Obesidade/imunologia , Obesidade/patologia , Humanos , Inflamação/patologia , Obesidade/epidemiologia , Fatores de Risco , SARS-CoV-2/imunologia
8.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445379

RESUMO

Chronic inflammation of the adipose tissue (AT) is a critical component of obesity-induced insulin resistance and type 2 diabetes. Adipose tissue immune cells, including AT macrophages (ATMs), AT dendritic cells (ATDCs), and T cells, are dynamically regulated by obesity and participate in obesity-induced inflammation. Among AT resident immune cells, ATDCs are master immune regulators and engage in crosstalk with various immune cells to initiate and regulate immune responses. However, due to confounding markers and lack of animal models, their exact role and contribution to the initiation and maintenance of AT inflammation and insulin resistance have not been clearly elucidated. This paper reviews the current understanding of ATDCs and their role in obesity-induced AT inflammation. We also provide the potential mechanisms by which ATDCs regulate AT inflammation and insulin resistance in obesity. Finally, this review offers perspectives on ways to better dissect the distinct functions and contributions of ATDCs to obesity.


Assuntos
Tecido Adiposo/citologia , Diabetes Mellitus Tipo 2/etiologia , Resistência à Insulina/imunologia , Obesidade/imunologia , Tecido Adiposo/imunologia , Animais , Apresentação do Antígeno , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 2/imunologia , Humanos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL
9.
Front Immunol ; 12: 650768, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248937

RESUMO

The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.


Assuntos
Imunidade Adaptativa/imunologia , Adipócitos/imunologia , Tecido Adiposo/imunologia , Imunidade Inata/imunologia , Obesidade/imunologia , Adipócitos/citologia , Adipócitos/metabolismo , Adipocinas/imunologia , Adipocinas/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
10.
Obesity (Silver Spring) ; 29(10): 1575-1579, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34212511

RESUMO

The position statement is issued by The Obesity Society in response to published literature, as well as inquiries made to the Society by patients, providers, Society members, policy makers, and others regarding the efficacy of vaccines in persons with obesity against SARS-CoV-2, the virus that causes COVID-19. The Obesity Society has critically evaluated data from published peer-reviewed literature and briefing documents from Emergency Use Authorization applications submitted by Pfizer-BioNTech, Moderna, and Johnson & Johnson. We conclude that these vaccines are highly efficacious, and their efficacy is not significantly different in people with and without obesity, based on scientific evidence available at the time of publication. The Obesity Society believes there is no definitive way to determine which of these three COVID-19 vaccines is "best" for any weight subpopulation (because of differences in the trial design and outcome measures in the phase 3 trials, elapsed time between doses, and regional differences in the presence of SARS-CoV-2 variants [e.g., South Africa B.1.351 in Johnson & Johnson trial]). All three trials have demonstrated high efficacy against COVID-19-associated hospitalization and death. Therefore, The Obesity Society encourages adults with obesity ≥18 years (≥16 years for Pfizer-BioNTech) to undergo vaccination with any one of the currently available vaccines authorized for emergency use by the US Food and Drug Administration as soon as they are able.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Obesidade/imunologia , SARS-CoV-2/imunologia , Sociedades Médicas , Adolescente , Adulto , Idoso , COVID-19/virologia , Ensaios Clínicos como Assunto , Humanos , Pessoa de Meia-Idade , Adulto Jovem
11.
Front Immunol ; 12: 670566, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220817

RESUMO

White adipose tissue (AT) contributes significantly to inflammation - especially in the context of obesity. Several of AT's intrinsic features favor its key role in local and systemic inflammation: (i) large distribution throughout the body, (ii) major endocrine activity, and (iii) presence of metabolic and immune cells in close proximity. In obesity, the concomitant pro-inflammatory signals produced by immune cells, adipocytes and adipose stem cells help to drive local inflammation in a vicious circle. Although the secretion of adipokines by AT is a prime contributor to systemic inflammation, the lipotoxicity associated with AT dysfunction might also be involved and could affect distant organs. In HIV-infected patients, the AT is targeted by both HIV infection and antiretroviral therapy (ART). During the primary phase of infection, the virus targets AT directly (by infecting AT CD4 T cells) and indirectly (via viral protein release, inflammatory signals, and gut disruption). The initiation of ART drastically changes the picture: ART reduces viral load, restores (at least partially) the CD4 T cell count, and dampens inflammatory processes on the whole-body level but also within the AT. However, ART induces AT dysfunction and metabolic side effects, which are highly dependent on the individual molecules and the combination used. First generation thymidine reverse transcriptase inhibitors predominantly target mitochondrial DNA and induce oxidative stress and adipocyte death. Protease inhibitors predominantly affect metabolic pathways (affecting adipogenesis and adipocyte homeostasis) resulting in insulin resistance. Recently marketed integrase strand transfer inhibitors induce both adipocyte adipogenesis, hypertrophy and fibrosis. It is challenging to distinguish between the respective effects of viral persistence, persistent immune defects and ART toxicity on the inflammatory profile present in ART-controlled HIV-infected patients. The host metabolic status, the size of the pre-established viral reservoir, the quality of the immune restoration, and the natural ageing with associated comorbidities may mitigate and/or reinforce the contribution of antiretrovirals (ARVs) toxicity to the development of low-grade inflammation in HIV-infected patients. Protecting AT functions appears highly relevant in ART-controlled HIV-infected patients. It requires lifestyle habits improvement in the absence of effective anti-inflammatory treatment. Besides, reducing ART toxicities remains a crucial therapeutic goal.


Assuntos
Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Animais , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Obesidade/imunologia , Obesidade/metabolismo
12.
Biomolecules ; 11(6)2021 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-34202969

RESUMO

Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the last decades, obesity and leptin have been associated with the initiation, proliferation and progression of many types of cancer. Obesity is also linked with complications and mortality, irrespective of the therapy used, affecting clinical outcomes. However, some evidence has suggested its beneficial role, called the "obesity paradox", and the possible antitumoral role of leptin. Recent data regarding the immunotherapy of cancer have revealed that overweight leads to a more effective response and leptin may probably be involved in this beneficial process. Since leptin is a positive modulator of both the innate and the adaptive immune system, it may contribute to the increased immune response stimulated by immunotherapy in cancer patients and may be proposed as a good actor in cancer. Our purpose is to review this dual role of leptin in cancer, as well as trying to clarify the future perspectives of this adipokine, which further highlights its importance as a cornerstone of the immunometabolism in oncology.


Assuntos
Imunidade Adaptativa , Imunoterapia , Leptina/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Humanos , Obesidade/imunologia
13.
Science ; 373(6550)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34210853

RESUMO

The mechanisms by which macrophages regulate energy storage remain poorly understood. We identify in a genetic screen a platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF)-family ortholog, Pvf3, that is produced by macrophages and is required for lipid storage in fat-body cells of Drosophila larvae. Genetic and pharmacological experiments indicate that the mouse Pvf3 ortholog PDGFcc, produced by adipose tissue-resident macrophages, controls lipid storage in adipocytes in a leptin receptor- and C-C chemokine receptor type 2-independent manner. PDGFcc production is regulated by diet and acts in a paracrine manner to control lipid storage in adipose tissues of newborn and adult mice. At the organismal level upon PDGFcc blockade, excess lipids are redirected toward thermogenesis in brown fat. These data identify a macrophage-dependent mechanism, conducive to the design of pharmacological interventions, that controls energy storage in metazoans.


Assuntos
Adipócitos/imunologia , Dieta Hiperlipídica , Proteínas de Drosophila/metabolismo , Metabolismo Energético , Linfocinas/metabolismo , Macrófagos/imunologia , Obesidade/imunologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Termogênese , Tecido Adiposo Marrom/imunologia , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Feminino , Hemócitos/imunologia , Fígado/imunologia , Linfocinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Crescimento Derivado de Plaquetas/genética , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299338

RESUMO

Obesity manifests itself with low-grade chronic inflammation that shapes immune responses during infection. Albeit obese individuals are at risk of higher mortality due to comorbidities, they are better protected from systemic inflammation. Recently, we showed that in the vasculature of obese mice kept on high-fat diet (HFD), neutrophils produce less neutrophil extracellular traps (NETs) than in lean controls (normal diet, ND). NETs are used by neutrophils to counteract severe infection, but they also cause collateral damage. Hardly anything is known about metabolic requirements for their formation, especially in the context of obesity and/or sepsis. Thus, we aimed to study the immunometabolism of NET formation by application of ex vivo neutrophil analyses (Seahorse analyzer, selective inhibitors, confocal imaging) and intravital microscopy. The obtained data show that glycolysis and/or pentose phosphate pathway are involved in NETs release by ND neutrophils in both physiological and inflammatory conditions. In contrast, such cells of septic HFD mice utilize these routes only to spontaneously cast NETs, while after secondary ex vivo activation they exhibit so called "exhausted phenotype", which manifests itself in diminished NET release despite high glycolytic potential and flexibility to oxidize fatty acids. Moreover, impact of ATP synthase inhibition on NET formation is revealed. Overall, the study shows that the neutrophil potential to cast NETs depends on both the metabolic and inflammatory state of the individual.


Assuntos
Armadilhas Extracelulares/metabolismo , Obesidade/metabolismo , Animais , Dieta Hiperlipídica , Armadilhas Extracelulares/imunologia , Glicólise , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Obesidade/imunologia , Obesidade/patologia , Via de Pentose Fosfato , Sepse/metabolismo
15.
Clin Nutr ESPEN ; 44: 475-478, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34330510

RESUMO

BACKGROUND & AIMS: Obesity is associated with low grade systemic inflammation and insulin resistance. Although metabolic and immunological changes may contribute to the increased risk for COVID-19 mortality in obese, little is known about the impact of obesity in the lungs of patients with COVID-19. METHODS: We analyzed gene expression profiles of autopsy lungs of a cohort of 14 COVID-19 patients and 4 control individuals. Patients were divided into 3 groups according to their comorbidities: hypertension, type 2 diabetes (T2D) and obesity. We then identified the molecular alterations associated with these comorbidities in COVID-19 patients. RESULTS: Patients with only hypertension showed higher levels of inflammatory genes and B-cell related genes when compared to those with T2D and obesity. However, the levels of IFN-gamma, IL22, and CD274 (a ligand that binds to receptor PD1) were higher in COVID-19 patients with T2D and obesity. Several metabolic- and immune-associated genes such as G6PD, LCK and IL10 were significantly induced in the lungs of the obese group. CONCLUSION: Our findings suggest that SARS-CoV-2 infection in the lungs may exacerbate the immune response and chronic condition in obese COVID-19 patients.


Assuntos
COVID-19/complicações , COVID-19/genética , Expressão Gênica/genética , Pulmão/imunologia , Obesidade/complicações , Obesidade/genética , Autopsia , COVID-19/imunologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Humanos , Hipertensão/complicações , Hipertensão/genética , Hipertensão/imunologia , Obesidade/imunologia , SARS-CoV-2
16.
J Immunol ; 207(4): 1200-1210, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34321227

RESUMO

Esophagogastric adenocarcinomas (EAC) are obesity-associated malignancies underpinned by severe immune dysregulation and inflammation. Our previous work indicates that NK cells migrate to EAC omentum, where they undergo phenotypic and functional alterations and apoptosis. In this study, we investigate whether such erroneous chemotaxis to omentum is paralleled by compromised NK cell infiltration of EAC patient tumor and examine the role of the inflammatory chemokine fractalkine in shaping the NK cell-mediated response. Our data show diminished NK cell frequencies in EAC tumor compared with those in the circulation and reveal that intratumoral NK cell frequencies decline as visceral obesity increases in EAC patients. Our in vitro findings demonstrate that antagonism of fractalkine receptor CX3CR1 significantly reduces NK cell migration to EAC patient-derived, omental adipose tissue-conditioned media, but not toward tumor-conditioned media. These data suggest fractalkine is a key driver of NK cell chemotaxis to omentum but has a lesser role in NK cell homing to tumor in EAC. We propose that this may offer a novel therapeutic strategy to limit NK cell depletion in the omentum of obese EAC patients, and our data suggest the optimal timing for CX3CR1 antagonism is after neoadjuvant chemoradiotherapy. Our functional studies demonstrate that fractalkine induces the conversion from CX3CR1+CD27- to CX3CR1-CD27+ NK cells and increases their IFN-γ and TNF-α production, indicative of its role in shaping the dominant NK cell phenotype in EAC omentum. This study uncovers crucial and potentially druggable pathways underpinning NK cell dysfunction in obesity-associated cancer and provides compelling insights into fractalkine's diverse biological functions.


Assuntos
Quimiocina CX3CL1/imunologia , Quimiotaxia/imunologia , Células Matadoras Naturais/imunologia , Obesidade/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Adenocarcinoma/imunologia , Tecido Adiposo/imunologia , Movimento Celular/imunologia , Neoplasias Esofágicas/imunologia , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptores de Quimiocinas/imunologia , Neoplasias Gástricas/imunologia
17.
Front Immunol ; 12: 666344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34108967

RESUMO

Adipose tissue is comprised of heterogenous cell populations that regulate both energy metabolism and immune reactions. Macrophages play critical roles in regulating immunometabolic homeostasis or disorders through cooperation with adipocytes, adipose tissue-derived stem cells (ADSCs) or other cells in adipose tissue. Extracellular vesicles (EVs) are recently recognized as efficient messengers for intercellular communication. Emerging evidences have demonstrated that adipose EVs are actively involved in the mutual interactions of macrophages, adipocytes and ADSCs, which produce considerable influences on immunometabolism under healthy or obese conditions. Here, we will elaborate the production and the characteristics of adipose EVs that are related to macrophages under different metabolic demands or stresses, whilst discuss the roles of these EVs in regulating local or systemic immunometabolic homeostasis or disorders in the context of adipocyte-macrophage dialogue and ADSC-macrophage interaction. Particularly, we provide a profile of dynamic adipose microenvironments based on macrophages. Adipose EVs act as the messengers between ADSCs and macrophages to maintain the balance of metabolism and immunity, while drive a vicious cycle between hypertrophic adipocytes and inflammatory macrophages to cause immunometabolic imbalance. This review may provide valuable information about the physio- or pathological roles of adipose EVs and the application of adipose EVs in the diagnosis and treatment of metabolic diseases.


Assuntos
Tecido Adiposo/imunologia , Vesículas Extracelulares/imunologia , Homeostase/imunologia , Macrófagos/imunologia , Obesidade/imunologia , Adipócitos/citologia , Adipócitos/imunologia , Tecido Adiposo/citologia , Comunicação Celular , Humanos , Macrófagos/citologia , Obesidade/patologia , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/imunologia
18.
Arch Biochem Biophys ; 708: 108951, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34102165

RESUMO

Obesity is a syndemia that promotes high expenditures for public health, and is defined by the excess of adipose tissue that is classified according to its function and anatomical distribution. In obese people, this tissue generates oxidative stress associated with a chronic inflammatory response, in which there is an imbalance in relation to the release of hormones and adipokines that cause loss of body homeostasis and predisposition to the development of some comorbidities. The purpose of this review is to summarize the main events that occur during the onset and progression of obesity with a special focus on biochemical and immunological changes. Hypertrophied and hyperplasia adipocytes have biomarkers and release adipokines capable of regulating pathways and expressing genes that culminate in the development of metabolic changes, such as changes in energy balance and intestinal microbiota, and the development of some comorbidities, diabetes mellitus, dyslipidemias, arterial hypertension, liver disease, cancer, allergies, osteoporosis, sarcopenia and obstructive sleep apnea. Thus, it is necessary to treat and/or prevent pathology, using traditional methods based on healthy eating, and regular physical and leisure activities.


Assuntos
Obesidade/imunologia , Obesidade/metabolismo , Animais , Humanos , Obesidade/patologia , Obesidade/terapia
19.
Front Immunol ; 12: 629391, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122403

RESUMO

Little is known about the involvement of type 2 immune response-promoting intestinal tuft cells in metabolic regulation. We here examined the temporal changes in small intestinal tuft cell number and activity in response to high-fat diet-induced obesity in mice and investigated the relation to whole-body energy metabolism and the immune phenotype of the small intestine and epididymal white adipose tissue. Intake of high fat diet resulted in a reduction in overall numbers of small intestinal epithelial and tuft cells and reduced expression of the intestinal type 2 tuft cell markers Il25 and Tslp. Amongst >1,700 diet-regulated transcripts in tuft cells, we observed an early association between body mass expansion and increased expression of the gene encoding the serine protease inhibitor neuroserpin. By contrast, tuft cell expression of genes encoding gamma aminobutyric acid (GABA)-receptors was coupled to Tslp and Il25 and reduced body mass gain. Combined, our results point to a possible role for small intestinal tuft cells in energy metabolism via coupled regulation of tuft cell type 2 markers and GABA signaling receptors, while being independent of type 2 immune cell involvement. These results pave the way for further studies into interventions that elicit anti-obesogenic circuits via small intestinal tuft cells.


Assuntos
Metabolismo Energético , Células Epiteliais/metabolismo , Intestino Delgado/metabolismo , Obesidade/metabolismo , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Epiteliais/imunologia , Regulação da Expressão Gênica , Interleucinas/genética , Interleucinas/metabolismo , Intestino Delgado/imunologia , Masculino , Camundongos Endogâmicos C57BL , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/imunologia , Fenótipo , Receptores de GABA/genética , Receptores de GABA/metabolismo , Serpinas/genética , Serpinas/metabolismo , Transdução de Sinais , Fatores de Tempo , Ganho de Peso
20.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063496

RESUMO

Diet-induced obesity can originate from the dysregulated activity of hypothalamic neuronal circuits, which are critical for the regulation of body weight and food intake. The exact mechanisms underlying such neuronal defects are not yet fully understood, but a maladaptive cross-talk between neurons and surrounding microglial is likely to be a contributing factor. Functional and anatomical connections between microglia and hypothalamic neuronal cells are at the core of how the brain orchestrates changes in the body's metabolic needs. However, such a melodious interaction may become maladaptive in response to prolonged diet-induced metabolic stress, thereby causing overfeeding, body weight gain, and systemic metabolic perturbations. From this perspective, we critically discuss emerging molecular and cellular underpinnings of microglia-neuron communication in the hypothalamic neuronal circuits implicated in energy balance regulation. We explore whether changes in this intercellular dialogue induced by metabolic stress may serve as a protective neuronal mechanism or contribute to disease establishment and progression. Our analysis provides a framework for future mechanistic studies that will facilitate progress into both the etiology and treatments of metabolic disorders.


Assuntos
Microglia/metabolismo , Neurônios/metabolismo , Obesidade/etiologia , Animais , Comunicação Celular , Citocinas/metabolismo , Dieta/efeitos adversos , Humanos , Rede Nervosa , Obesidade/imunologia , Obesidade/metabolismo
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