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1.
Fish Shellfish Immunol ; 90: 338-348, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075404

RESUMO

N-Carbamylglutamate (NCG), an analogue of N-acetylglutamate (NAG), can promote the synthesis of endogenous Arginine (Arg) in mammals, but not well studied in fish. This study was conducted to investigate the capacity of Arg endogenous synthesis by NCG, and the effects of various dietary NCG doses on growth performance, hepatic health and underlying nutrient regulation metabolism on ERK1/2-mTOR-S6K1 signaling pathway in Japanese seabass (Lateolabrax japonicus). Four experimental diets were prepared with NCG supplement levels of 0 (N0), 360 (N360), 720 (N720) and 3600 (N3600) mg/kg, in which N360 was at the maximum recommended level authorized by MOA, China in fish feed, and the N720 and N3600 levels were 2 and 10-fold of N360, respectively. Each diet was fed to 6 replicates with 30 Japanese seabass (initial body weight, IBW = 11.67 ±â€¯0.02 g) in each tank. The results showed that the dietary NCG supplementation had no significant effects on the SGR and morphometric parameters of Japanese seabass, but 360-720 mg/kg NCG inclusion promoted PPV, while the 10-fold (3600 mg/kg) overdose of NCG had remarkably negative effects with significantly reduced feed efficiency, PPV and LPV. We found that Japanese seabass can utilize 360-720 mg/kg NCG to synthesis Arg to improve the amino acid metabolism by increasing plasma Arg and up-regulating intestinal ASL gene expression. Increased plasma GST and decreased MDA indicated the improved antioxidant response. Dietary NCG inclusion decreased plasma IgM and down-regulated the mRNA levels of inflammation (TNF-α and IL8), apoptosis (caspase family) and fibrosis (TGF-ß1) related genes in the liver. The immunofluorescence examination revealed significantly decreased hepatic apoptosis and necrosis signals in the NCG groups. The ameliorated liver function and histological structure were closely related to the improved lipid metabolism parameters with decreased plasma VLDL and hepatic TG and NEFA accumulation, down-regulated fatty acid and cholesterol synthesis and simultaneously increased lipolysis gene mRNA levels, which regulated by inhibiting phosphorylation of ERK1/2-mTOR-S6K1 signaling pathway. Consuming 3600 mg/kg of dietary NCG is not safe for Japanese seabass culturing with the significantly increased FCR and decreased protein and lipid retention, and reduced plasma ALB. Accordingly, the observed efficacy and safety level of dietary NCG in the diet of Japanese seabass is 720 mg/kg.


Assuntos
Bass , Doenças dos Peixes/prevenção & controle , Glutamatos/metabolismo , Hepatopatias/veterinária , Doenças Metabólicas/veterinária , Ração Animal/análise , Animais , Apoptose/efeitos dos fármacos , Arginina/biossíntese , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Glutamatos/administração & dosagem , Hepatócitos/efeitos dos fármacos , Hepatopatias/imunologia , Hepatopatias/prevenção & controle , Doenças Metabólicas/imunologia , Doenças Metabólicas/prevenção & controle , Nutrientes/metabolismo , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos
2.
Eur J Pharmacol ; 854: 272-281, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30974105

RESUMO

Diverse disturbances in immune-endocrine circuitries are involved in the development and aggravation of several chronic metabolic diseases (CMDs), including obesity, diabetes, and metabolic syndrome. The chronic inflammatory syndrome observed in CMDs culminates in dysregulated immune responses with low microbial killing efficiency, by means low host innate immune response, and loss of ability to eliminate the pathogens, which results in a high prevalence of infectious diseases, including pneumonia, tuberculosis, and sepsis. Herein, we review evidence pointing out PPARγ as a putative player in immune-endocrine disturbances related to increased risk of infections in CMDs. Cumulated evidence indicates that PPARγ activation modulates host cells to control inflammation during CMDs because of PPARγ agonists have anti-inflammatory and pro-resolutive properties, increasing host ability to eliminate pathogen, modulating hormone production, and restoring glucose and lipid homeostasis. As such, we propose PPARγ as a putative therapeutic adjuvant for patients with CMDs to favor a better infection control.


Assuntos
Sistema Endócrino/fisiopatologia , Infecção/complicações , Doenças Metabólicas/imunologia , Doenças Metabólicas/fisiopatologia , PPAR gama/metabolismo , Animais , Doença Crônica , Humanos , Doenças Metabólicas/complicações , Doenças Metabólicas/metabolismo , Risco
3.
Int J Mol Sci ; 19(12)2018 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-30558209

RESUMO

Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response-and interleukins-had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed.


Assuntos
Inflamação/metabolismo , Interleucinas/metabolismo , Lipídeos/imunologia , Doenças Metabólicas/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Humanos , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/metabolismo , Inflamação/tratamento farmacológico , Inflamação/imunologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/imunologia
4.
Gut ; 67(9): 1716-1725, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29934437

RESUMO

The microbiome has received increasing attention over the last 15 years. Although gut microbes have been explored for several decades, investigations of the role of microorganisms that reside in the human gut has attracted much attention beyond classical infectious diseases. For example, numerous studies have reported changes in the gut microbiota during not only obesity, diabetes, and liver diseases but also cancer and even neurodegenerative diseases. The human gut microbiota is viewed as a potential source of novel therapeutics. Between 2013 and 2017, the number of publications focusing on the gut microbiota was, remarkably, 12 900, which represents four-fifths of the total number of publications over the last 40 years that investigated this topic. This review discusses recent evidence of the impact of the gut microbiota on metabolic disorders and focus on selected key mechanisms. This review also aims to provide a critical analysis of the current knowledge in this field, identify putative key issues or problems and discuss misinterpretations. The abundance of metagenomic data generated on comparing diseased and healthy subjects can lead to the erroneous claim that a bacterium is causally linked with the protection or the onset of a disease. In fact, environmental factors such as dietary habits, drug treatments, intestinal motility and stool frequency and consistency are all factors that influence the composition of the microbiota and should be considered. The cases of the bacteria Prevotella copri and Akkermansia muciniphila will be discussed as key examples.


Assuntos
Microbioma Gastrointestinal/imunologia , Doenças Metabólicas/imunologia , Doenças Metabólicas/microbiologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/microbiologia , Disbiose/prevenção & controle , Medicina Baseada em Evidências , Humanos , Hepatopatias/imunologia , Hepatopatias/microbiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/prevenção & controle , Neoplasias/imunologia , Neoplasias/microbiologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/microbiologia , Obesidade/imunologia , Obesidade/microbiologia , Prevotella/imunologia , Verrucomicrobia/imunologia
5.
Cell Physiol Biochem ; 47(1): 1-10, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29763888

RESUMO

Hydrogen (H2) is colorless, odorless, and the lightest of gas molecules. Studies in the past ten years have indicated that H2 is extremely important in regulating the homeostasis of the cardiovascular system and metabolic activity. Delivery of H2 by various strategies improves cardiometabolic diseases, including atherosclerosis, vascular injury, ischemic or hypertrophic ventricular remodeling, intermittent hypoxia- or heart transplantation-induced heart injury, obesity and diabetes in animal models or in clinical trials. The purpose of this review is to summarize the physical and chemical properties of H2, and then, the functions of H2 with an emphasis on the therapeutic potential and molecular mechanisms involved in the diseases above. We hope this review will provide the future outlook of H2-based therapies for cardiometabolic disease.


Assuntos
Doenças Cardiovasculares/terapia , Hidrogênio/uso terapêutico , Doenças Metabólicas/terapia , Imunidade Adaptativa , Animais , Apoptose , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Humanos , Hidrogênio/administração & dosagem , Hidrogênio/metabolismo , Hidrogênio/farmacologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/terapia , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Estresse Oxidativo
6.
Trends Pharmacol Sci ; 39(6): 536-546, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29628274

RESUMO

Macrophages are cells of the innate immune system that are resident in all tissues, including metabolic organs such as the liver and adipose tissue (AT). Because of their phenotypic flexibility, they play beneficial roles in tissue homeostasis, but they also contribute to the progression of metabolic disease. Thus, they are ideal therapeutic targets for diseases such as insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Recently, discoveries in the area of drug delivery have facilitated phenotype-specific targeting of macrophages. In this review we discuss advances in potential therapeutics for metabolic diseases via macrophage-specific delivery. We highlight micro- and nanoparticles, liposomes, and oligopeptide complexes, and how they can be used to alter macrophage phenotype for a more metabolically favorable tissue environment.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Doenças Metabólicas/tratamento farmacológico , Preparações Farmacêuticas/administração & dosagem , Humanos , Macrófagos/imunologia , Doenças Metabólicas/imunologia , Terapia de Alvo Molecular
7.
J Microbiol ; 56(3): 154-162, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29492872

RESUMO

The intestinal microbiota is comprised of millions of microorganisms that reside in the gastrointestinal tract and consistently interact with the host. Host factors such as diet and disease status affect the composition of the microbiota, while the microbiota itself produces metabolites that can further manipulate host physiology. Dysbiosis of the intestinal microbiota has been characterized in patients with certain metabolic diseases, some of which involve damage to the host intestinal epithelial barrier and alterations in the immune system. In this review, we will discuss the consequences of dietdependent bacterial dysbiosis in the gastrointestinal tract, and how the associated interaction with epithelial and immune cells impacts metabolic diseases.


Assuntos
Bactérias/metabolismo , Microbioma Gastrointestinal/imunologia , Trato Gastrointestinal/imunologia , Sistema Imunitário/imunologia , Doenças Metabólicas/imunologia , Doenças Metabólicas/microbiologia , Animais , Fenômenos Fisiológicos Bacterianos , Dieta , Dieta Hiperlipídica/efeitos adversos , Disbiose , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/microbiologia , Humanos , Intestinos/citologia , Intestinos/imunologia , Intestinos/microbiologia , Doenças Metabólicas/etiologia , Camundongos
8.
Biochem Biophys Res Commun ; 500(1): 35-44, 2018 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-28647358

RESUMO

Living organisms have the capacity to sense both nutrients and immune signals in order to adapt their metabolism to the needs, and both metabolic inflexibility and exacerbated immune responses are associated with metabolic diseases. Over the past decade, mitochondria emerged as key nutrient and immune sensors regulating numerous signalling pathways, and mitochondria dysfunction has been extensively implicated in metabolic diseases. Interestingly, mitochondria interact physically and functionally with the endoplasmic reticulum (ER, in contact sites named mitochondria-associated membranes (MAMs), in order to exchange metabolites and calcium and regulate cellular homeostasis. Emerging evidences suggest that MAMs provide a platform for hormone and nutrient signalling pathways and for innate immune responses, then regulating mitochondrial bioenergetics and apoptosis. Here, I thus propose the concept that MAMs could be attractive nutrient and immune sensors that regulate mitochondria physiology in order to adapt metabolism and cell fate, and that organelle miscommunication could be involved in the metabolic inflexibility and the pro-inflammatory status associated with metabolic diseases.


Assuntos
Cálcio/metabolismo , Metabolismo Energético/imunologia , Doenças Metabólicas/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/imunologia , Membranas Mitocondriais/metabolismo , Animais , Apoptose/genética , Cálcio/imunologia , Sinalização do Cálcio/imunologia , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Homeostase , Humanos , Imunidade Inata , Resistência à Insulina/imunologia , Doenças Metabólicas/imunologia , Doenças Metabólicas/patologia , Mitocôndrias/imunologia , Membranas Mitocondriais/imunologia
9.
Gut ; 67(1): 157-165, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011892

RESUMO

OBJECTIVE: Low-grade chronic inflammation emerges as a potent driver of insulin resistance and glucose dysregulation in obesity and associated non-alcoholic fatty liver disease (NAFLD). The liver, subcutaneous fat and the immune system participate in disturbances of metabolism. Type I interferon (IFN) signalling initiated by innate and adaptive immunity modulates inflammatory responses consequent to infection. However, little is known about the role of type I IFN signalling in metabolic diseases and the development of NAFLD. DESIGN: We determined the impact of type I IFN signalling by tissue-specific deletion of interferon (α and ß) receptor 1 (Ifnar1) in hepatocytes (Ifnar1Δhep ), adipocytes (Ifnar1Δat ), intestinal epithelial cells (Ifnar1ΔIEC ) or myelocytes (Ifnar1Δmyel ) on glucose metabolism, obesity and hepatic disease in mice exposed to a high-fat or methionine-choline-deficient (MCD) diet. Furthermore, we investigated the expression of type I IFN-regulated genes in patients with obesity undergoing laparoscopic adjustable gastric banding (LAGB). RESULTS: Long chain fatty acids induce type I IFN responses in murine hepatocytes and macrophages and exposure to a high-fat diet elicited type I IFN-regulated gene expression in the liver of wild-type mice. Hepatocyte-specific, but not adipose tissue-specific deletion of Ifnar1 worsened steatosis and inflammation induced by the MCD diet. In contrast, adipose-specific, but not hepatocyte-specific deletion of Ifnar1 deteriorated metabolic dysregulation induced by a high-fat diet, indicated by increased weight gain, insulin resistance and an impaired glucose tolerance. Abrogated type I IFN signalling in myeloid or intestinal epithelial cells did not modulate susceptibility to metabolic or hepatic disease. Improved metabolic control in patients with obesity after LAGB was associated with increased expression of type I IFN-regulated genes in subcutaneous adipose tissue and liver. CONCLUSIONS: Our study implicates a role for adipose and hepatocyte type I IFN signalling in diet-induced metabolic dysregulation and hepatic disease. Further studies on type I IFN signalling in metabolic diseases are warranted.


Assuntos
Tecido Adiposo/imunologia , Interferon Tipo I/imunologia , Doenças Metabólicas/prevenção & controle , Obesidade/imunologia , Adulto , Idoso , Animais , Glicemia/metabolismo , Células Cultivadas , Dieta Hiperlipídica , Feminino , Gastroplastia , Regulação da Expressão Gênica/imunologia , Intolerância à Glucose/imunologia , Hepatócitos/imunologia , Humanos , Fígado/imunologia , Macrófagos/imunologia , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Doenças Metabólicas/imunologia , Camundongos Knockout , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/complicações , Obesidade Mórbida/genética , Obesidade Mórbida/imunologia , Obesidade Mórbida/cirurgia , Período Pós-Operatório , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais/imunologia , Adulto Jovem
10.
Biochem Biophys Res Commun ; 494(3-4): 648-655, 2017 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-29079192

RESUMO

A large amount of fructose intake along with smoking is associated with increased incidence of diseases linked to metabolic syndrome. More research is necessary to understand the complex mechanism that ultimately results in metabolic syndrome and the effect, if any, of high fructose dietary intake and smoking on individual health. In this study, we investigated changes in ER-Golgi network and disturbance to secretion of adipokines induced by cigarette smoking (CS) and excess fructose intake and their contribution to the disruption of metabolic homeostasis. We used high fructose-induced metabolic disorder mice model by feeding them with high fructose diet for 8 weeks. For CS exposure experiment, these mice were exposed to CS for 28 days according to OECD guideline 412. Our results clearly showed that the immune system was suppressed and ER stress was induced in mice with exposure to CS and fed with high fructose. Furthermore, their concentrations of adipokines including leptin and adiponectin were aberrant. Such alteration in secretion of adipokines could cause insulin resistance which may lead to the development of type 2 diabetes.


Assuntos
Adipocinas/imunologia , Adipocinas/metabolismo , Apoptose/efeitos dos fármacos , Fumar Cigarros/efeitos adversos , Resistência à Insulina/imunologia , Doenças Metabólicas/imunologia , Animais , Açúcares da Dieta , Frutose , Masculino , Doenças Metabólicas/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Poluição por Fumaça de Tabaco/efeitos adversos
11.
Adv Neurobiol ; 19: 3-31, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28933059

RESUMO

Adipose tissue is an endocrine organ which is responsible for postprandial uptake of glucose and fatty acids, consequently producing a broad range of adipokines controlling several physiological functions like appetite, insulin sensitivity and secretion, immunity, coagulation, and vascular tone, among others. Many aspects of adipose tissue pathophysiology in metabolic diseases have been described in the last years. Recent data suggest two main factors for adipose tissue dysfunction: accumulation of nonesterified fatty acids and their secondary products and hypoxia. Both of these factors are thought to be on the basis of low-grade inflammatory activation, further increasing metabolic dysregulation in adipose tissue. In turn, inflammation is involved in the inhibition of substrate uptake, alteration of the secretory profile, stimulation of angiogenesis, and recruitment of further inflammatory cells, which creates an inflammatory feedback in the tissue and is responsible for long-term establishment of insulin resistance.


Assuntos
Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Ácidos Graxos/metabolismo , Glucose/metabolismo , Hipóxia/metabolismo , Resistência à Insulina/fisiologia , Neovascularização Patológica/metabolismo , Adipocinas/fisiologia , Tecido Adiposo/imunologia , Tecido Adiposo/fisiologia , Apetite/fisiologia , Transporte Biológico , Coagulação Sanguínea/fisiologia , Vasos Sanguíneos/fisiologia , Ácidos Graxos não Esterificados/metabolismo , Retroalimentação Fisiológica , Humanos , Inflamação/imunologia , Resistência à Insulina/imunologia , Metabolismo dos Lipídeos , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Neovascularização Patológica/imunologia
12.
Immunity ; 47(3): 406-420, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28930657

RESUMO

Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health.


Assuntos
Metabolismo Energético , Imunidade , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Imunidade Adaptativa , Animais , Evolução Biológica , Comunicação Celular/imunologia , Citocinas/metabolismo , Glucose/metabolismo , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade Inata , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação , Doenças Metabólicas/terapia , Especificidade de Órgãos , Transdução de Sinais , Pesquisa Médica Translacional
13.
Biol Aujourdhui ; 211(1): 1-18, 2017.
Artigo em Francês | MEDLINE | ID: mdl-28682223

RESUMO

The aim of the review is to discuss about the role played by the defence crosstalk between the gut microbiota and the intestinal immune system, in the development of metabolic disease focusing on obesity and diabetes. Starting from physiological and pathological stand points and based on the latest published data, this review is addressing how the concept of the hologenome theory of evolution can drive the fate of metabolic disease. The notion of "metabolic infection" to explain the "metabolic inflammation" is discussed. This imply comments about the process of bacterial translocation and impaired intestinal immune defense against commensals. Eventually this review sets the soil for personalized medicine. The monthly increase in the number of publications on the gut microbiota to intestinal immune defense and the control of metabolism demonstrate the importance of this field of investigation. The notion of commensal as "self or non-self" has to be reevaluated in the light of the current data. Furthermore, data demonstrate the major role played by short chain fatty acids, secondary bile acids, LPS, peptidoglycans, indole derivatives, and other bacteria-related molecules on the shaping of cells involved in the intestinal protection against commensals is now becoming a central player in the incidence of metabolic diseases. The literature demonstrates that the onset of metabolic diseases and some specific co-morbidities can be explained by a gut microbiota to intestinal immune system crosstalk. Therefore, one should now consider this avenue of investigation as a putative source of biomarkers and therapeutic targets to personalize the treatment of metabolic disease and its co-morbidities. Gut microbiota is considered as a major regulator of metabolic disease. This reconciles the notion of metabolic inflammation and the epidemic development of the disease. In addition to evidence showing that a specific gut microbiota characterizes patients with obesity, type 2 diabetes, and hepatic steatosis, the mechanisms causal to the disease could be related to the translocation of microbiota from the gut to the tissues, which induces inflammation. The mechanisms regulating such a process are based on the crosstalk between the gut microbiota and the host immune system. The hologenome theory of evolution supports this concept and implies that therapeutic strategies aiming to control glycemia should take into account both the gut microbiota and the host immune system. This review discusses the latest evidence regarding the bidirectional impact of the gut microbiota on host immune system crosstalk for the control of metabolic disease, hyperglycemia, and obesity. To avoid redundancies with the literature, we will focus our attention on the intestinal immune system, identifying evidence for the generation of novel therapeutic strategies, which could be based on the control of the translocation of gut bacteria to tissues. Such novel strategies should hamper the role played by gut microbiota dysbiosis on the development of metabolic inflammation. Recent evidence in rodents allows us to conclude that an impaired intestinal immune system characterizes and could be causal in the development of metabolic disease. The fine understanding of the molecular mechanisms should allow for the development of a first line of treatment for metabolic disease and its co-morbidities.


Assuntos
Microbioma Gastrointestinal/fisiologia , Sistema Imunitário/fisiologia , Doenças Metabólicas/imunologia , Doenças Metabólicas/microbiologia , Animais , Disbiose/complicações , Disbiose/imunologia , Disbiose/microbiologia , Disbiose/prevenção & controle , Microbioma Gastrointestinal/imunologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/metabolismo , Humanos , Inflamação/etiologia , Inflamação/microbiologia , Doenças Metabólicas/metabolismo , Transdução de Sinais/imunologia
15.
Arthritis Res Ther ; 19(1): 127, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28587625

RESUMO

BACKGROUND: We determined the prevalence of anti-nuclear autoantibodies (ANAs) in the German adult population and examined the association between ANAs and cardiovascular and metabolic disorders. METHODS: We used data and blood samples from the pretest phases of the German National Cohort, obtained from six of the 18 study centers (n = 1199). All centers applied standardized instruments including face-to-face interviews, anthropometric measurements and collection of blood samples. Self-reported histories of diabetes mellitus, heart attack and elevated blood cholesterol and/or lipids were recorded. Height, weight and blood pressure were measured. ANAs were detected using a semi-automated system (AKLIDES®; Medipan GmbH, Dahlewitz, Germany). A positive ANA was defined as a titer ≥ 1:80. ANA were classified as weakly (1:80 or 1:160), moderately (1:320 or 1:640) or strongly (≥1:1280) positive. Specific autoantibodies against nuclear antigens were detected with second-step assays according to the ANA staining pattern. Associations between the assessed disorders and ANA positivity and pattern were examined using sex and age-adjusted mixed-effects logistic regression models. RESULTS: Thirty-three percent (95% confidence interval; 31-36%) of the 1196 participants (measurements could not be obtained from three samples) were ANA positive (titer ≥ 1:80). The proportions of weakly, moderately and strongly positive ANA were 29%, 3.3% and 1.3%, respectively. ANA positivity was more common among women than men across all titers (χ2, p = 0.03). ANA positivity, even when stratified according to height of titer or immunofluorescent pattern, was not associated with diabetes, elevated blood cholesterol and/or lipids, obesity or hypertension. Second-step autoantibody assays were positive in 41 of the 83 samples (49%) tested, with anti-DFS70 (n = 13) and anti-dsDNA (n = 7) being most frequent. These subgroups were too small to test for associations with the disorders assessed. CONCLUSIONS: The prevalence of ANA positivity in the German general population was similar to values reported from other countries. Contrary to other studies, there was no association with selected self-reported and objectively measured cardiovascular and metabolic variables.


Assuntos
Anticorpos Antinucleares/imunologia , Doenças Cardiovasculares/imunologia , Doenças Metabólicas/imunologia , Vigilância da População/métodos , Adulto , Idoso , Anticorpos Antinucleares/sangue , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Feminino , Alemanha/epidemiologia , Humanos , Lipídeos/sangue , Modelos Logísticos , Masculino , Doenças Metabólicas/epidemiologia , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
16.
Dialogues Clin Neurosci ; 19(1): 19-26, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28566944

RESUMO

The recognition of altered immune system function in many chronic disease states has proven to be a pivotal advance in biomedical research over the past decade. For many metabolic and mood disorders, this altered immune activity has been characterized as inflammation, with the attendant assumption that the immune response is aberrant. However, accumulating evidence challenges this assumption and suggests that the immune system may be mounting adaptive responses to chronic stressors. Further, the inordinate complexity of immune function renders a simplistic, binary model incapable of capturing critical mechanistic insights. In this perspective article, we propose alternative paradigms for understanding the role of the immune system in chronic disease. By invoking allostasis or systems biology rather than inflammation, we can ascribe greater functional significance to immune mediators, gain newfound appreciation of the adaptive facets of altered immune activity, and better avoid the potentially disastrous effects of translating erroneous assumptions into novel therapeutic strategies.


Assuntos
Adaptação Fisiológica/imunologia , Sistema Imunitário/imunologia , Doenças Metabólicas/imunologia , Transtornos do Humor/imunologia , Adaptação Fisiológica/fisiologia , Alostase/imunologia , Alostase/fisiologia , Doença Crônica , Humanos , Sistema Imunitário/fisiopatologia , Inflamação/imunologia , Inflamação/fisiopatologia , Doenças Metabólicas/fisiopatologia , Transtornos do Humor/fisiopatologia
17.
Sci Transl Med ; 9(396)2017 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-28659437

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is now the most common progressive liver disease in developed countries and is the second leading indication for liver transplantation due to the extensive fibrosis it causes. NAFLD progression is thought to be tied to chronic low-level type 1 inflammation originating in the adipose tissue during obesity; however, the specific immunological mechanisms regulating the progression of NAFLD-associated fibrosis in the liver are unclear. To investigate the immunopathogenesis of NAFLD more completely, we investigated adipose dysfunction, nonalcoholic steatohepatitis (NASH), and fibrosis in mice that develop polarized type 1 or type 2 immune responses. Unexpectedly, obese interleukin-10 (IL-10)/IL-4-deficient mice (type 1-polarized) were highly resistant to NASH. This protection was associated with an increased hepatic interferon-γ (IFN-γ) signature. Conversely, IFN-γ-deficient mice progressed rapidly to NASH with evidence of fibrosis dependent on transforming growth factor-ß (TGF-ß) and IL-13 signaling. Unlike increasing type 1 inflammation and the marked loss of eosinophils seen in expanding adipose tissue, progression of NASH was associated with increasing eosinophilic type 2 liver inflammation in mice and human patient biopsies. Finally, simultaneous inhibition of TGF-ß and IL-13 signaling attenuated the fibrotic machinery more completely than TGF-ß alone in NAFLD-associated fibrosis. Thus, although type 2 immunity maintains healthy metabolic signaling in adipose tissues, it exacerbates the progression of NAFLD collaboratively with TGF-ß in the liver.


Assuntos
Progressão da Doença , Imunidade , Doenças Metabólicas/imunologia , Doenças Metabólicas/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Fator de Crescimento Transformador beta/metabolismo , Tecido Adiposo/patologia , Animais , Dieta Hiperlipídica , Eosinófilos/patologia , Humanos , Inflamação/patologia , Interferon gama/deficiência , Interferon gama/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/patologia
18.
Eur J Clin Nutr ; 71(7): 904-912, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28402325

RESUMO

Diabetes mellitus is one of the most common chronic metabolic disorders worldwide, and its incidence in Asian countries is alarmingly high. Type 2 diabetes (T2DM) is closely associated with obesity, and the staggering rise in obesity is one of the primary factors related to the increased frequency of T2DM. Low-grade chronic inflammation is also accepted as an integral metabolic adaption in obesity and T2DM, and is believed to be a major player in the onset of insulin resistance. However, the exact mechanism(s) that cause a persistent chronic low-grade infiltration of leukocytes into insulin-target tissues such as adipose, skeletal muscle and liver are not entirely known. Recent developments in the understanding of leukocyte metabolism have revealed that the inflammatory polarization of immune cells, and consequently their immunological function, are strongly connected to their metabolic profile. Therefore, it is hypothesized that dysfunctional immune cell metabolism is a central cellular mechanism that prevents the resolution of inflammation in chronic metabolic conditions such as that observed in obesity and T2DM. The purpose of this review is to explore the metabolic demands of different immune cell types, and identify the molecular switches that control immune cell metabolism and ultimately function. Understanding of these concepts may allow the development of interventions that can correct immune function and may possibly decrease chronic low-grade inflammation in humans suffering from obesity and T2DM. We also review the latest clinical techniques used to measure metabolic flux in primary leukocytes isolated from obese and T2DM patients.


Assuntos
Imunidade Adaptativa , Diabetes Mellitus Tipo 2/imunologia , Metabolismo Energético , Inflamação/imunologia , Obesidade/imunologia , Animais , Doença Crônica , Modelos Animais de Doenças , Humanos , Imunidade Celular , Insulina/sangue , Resistência à Insulina , Leucócitos/metabolismo , Doenças Metabólicas/imunologia
19.
Nutrients ; 9(4)2017 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-28368340

RESUMO

Postprandial inflammation and endotoxaemia are determinants of cardiovascular and metabolic disease risk which are amplified by high fat meals. We aimed to examine the determinants of postprandial inflammation and endotoxaemia in older and younger adults following a high fat mixed meal. In a randomised cross-over trial, healthy participants aged 20-25 and 60-75 years (n = 15/group) consumed a high-fat breakfast and a low-fat breakfast. Plasma taken at baseline and post-meal for 5 h was analysed for circulating endotoxin, cytokines (monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-1ß, IL-6, and tumour necrosis factor-alpha (TNF-α)), lipopolysaccharide binding protein (LBP), and inflammatory gene expression in peripheral blood mononuclear cells (PBMC). Older subjects had lower baseline PBMC expression of Glutathione peroxidase 1 (GPX-1) but greater insulin-like growth factor-binding protein 3 (IGFBP3) and circulating MCP-1 compared to younger subjects. After either meal, there were no age differences in plasma, chylomicron endotoxin, or plasma LBP concentrations, nor in inflammatory cytokine gene and protein expression (MCP-1, IL-1ß, and TNF-α). Unlike younger participants, the older group had decreased superoxide dismutase (SOD)-2 expression after the meals. After a high-fat meal, older adults have no increased inflammatory or endotoxin response, but an altered oxidative stress gene response compared with younger adults. Healthy older adults, without apparent metabolic dysfunction, have a comparable postprandial inflammatory and endotoxaemia response to younger adults.


Assuntos
Doenças Cardiovasculares/etiologia , Dieta Hiperlipídica/efeitos adversos , Fenômenos Fisiológicos da Nutrição do Idoso , Regulação da Expressão Gênica no Desenvolvimento , Leucócitos Mononucleares/metabolismo , Doenças Metabólicas/etiologia , Vasculite/etiologia , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Desjejum , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Estudos de Coortes , Estudos Cross-Over , Feminino , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/imunologia , Masculino , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Período Pós-Prandial , Fatores de Risco , Vasculite/imunologia , Vasculite/metabolismo , Vasculite/fisiopatologia , Adulto Jovem
20.
Immunobiology ; 222(10): 925-936, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28363498

RESUMO

This review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and autoimmunity. Multiple therapeutic approaches using existing pharmaceuticals are possible from a rationale in which T cell metabolism forms the hub in dampening the T cell component of autoimmunity in metabolic diseases. Future research into the effects of a metabolically aberrant micro-environment on T cell metabolism and its potential as a therapeutic target for immunomodulation could lead to novel treatment strategies for metabolic disease-associated autoimmunity.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade , Imunoterapia/métodos , Doenças Metabólicas/imunologia , Linfócitos T/metabolismo , Animais , Doenças Autoimunes/complicações , Microambiente Celular , Humanos , Doenças Metabólicas/complicações , Doenças Metabólicas/terapia , Linfócitos T/imunologia
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