RESUMO
UNASSIGNED: Excess body weight has become a global epidemic and a significant risk factor for developing chronic diseases, which are the leading causes of worldwide morbidities. Adipose tissue (AT), primarily composed of adipocytes, stores substantial amounts of energy and plays a crucial role in maintaining whole-body glucose and lipid metabolism. This helps prevent excessive body fat accumulation and lipotoxicity in peripheral tissues. In addition, AT contains endothelial cells and a substantial population of immune cells (constituting 60-70% of non-adipocyte cells), including macrophages, T and B lymphocytes, and natural killer cells. These resident immune cells engage in crosstalk with adipocytes, contributing to the maintenance of metabolic and immune homeostasis in AT. An exacerbated inflammatory response or inadequate immune resolution can lead to chronic systemic low-grade inflammation, triggering the development of metabolic alterations and the onset of chronic diseases. This review aims to elucidate the regulatory mechanisms through which immune cells influence AT function and energy homeostasis. We also focus on the interactions and functional dynamics of immune cell populations, highlighting their role in maintaining the delicate balance between metabolic health and obesity-related inflammation. Finally, understanding immunometabolism is crucial for unraveling the pathogenesis of metabolic diseases and developing targeted immunotherapeutic strategies. These strategies may offer innovative avenues in the rapidly evolving field of immunometabolism. (Rev Invest Clin. 2024;76(2):65-79).
Assuntos
Tecido Adiposo , Inflamação , Doenças Metabólicas , Obesidade , Humanos , Tecido Adiposo/metabolismo , Tecido Adiposo/imunologia , Obesidade/imunologia , Obesidade/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/etiologia , Metabolismo Energético/fisiologia , Adipócitos/metabolismo , Adipócitos/imunologia , Metabolismo dos Lipídeos/fisiologia , Animais , HomeostaseRESUMO
Innate immune cells can develop exacerbated immunologic response and long-term inflammatory phenotype following brief exposure to endogenous or exogenous insults, which leads to an altered response towards a second challenge after the return to a nonactivated state. This phenomenon is known as trained immunity (TI). TI is not only important for host defense and vaccine response but also for chronic inflammations such as cardiovascular and metabolic diseases such as atherosclerosis. TI can occur in innate immune cells such as monocytes/macrophages, natural killer cells, endothelial cells (ECs), and nonimmune cells, such as fibroblast. In this brief review, we analyze the significance of TI in ECs, which are also considered as innate immune cells in addition to macrophages. TI can be induced by a variety of stimuli, including lipopolysaccharides, BCG (bacillus Calmette-Guerin), and oxLDL (oxidized low-density lipoprotein), which are defined as risk factors for cardiovascular and metabolic diseases. Furthermore, TI in ECs is functional for inflammation effectiveness and transition to chronic inflammation. Rewiring of cellular metabolism of the trained cells takes place during induction of TI, including increased glycolysis, glutaminolysis, increased accumulation of tricarboxylic acid cycle metabolites and acetyl-coenzyme A production, as well as increased mevalonate synthesis. Subsequently, this leads to epigenetic remodeling, resulting in important changes in chromatin architecture that enables increased gene transcription and enhanced proinflammatory immune response. However, TI pathways and inflammatory pathways are separated to ensure memory stays when inflammation undergoes resolution. Additionally, reactive oxygen species play context-dependent roles in TI. Therefore, TI plays significant roles in EC and macrophage pathology and chronic inflammation. However, further characterization of TI in ECs and macrophages would provide novel insights into cardiovascular disease pathogenesis and new therapeutic targets. Graphic Abstract: A graphic abstract is available for this article.
Assuntos
Células Endoteliais/imunologia , Macrófagos/imunologia , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Citocinas/biossíntese , Metabolismo Energético , Epigênese Genética , Humanos , Imunidade Inata , Memória Imunológica , Infecções/etiologia , Infecções/imunologia , Inflamação/etiologia , Inflamação/imunologia , Doenças Metabólicas/etiologia , Doenças Metabólicas/imunologia , Redes e Vias Metabólicas/imunologia , Modelos Imunológicos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/imunologia , Fatores de RiscoRESUMO
Adipose tissue is considered an endocrine organ whose complex biology can be explained by the diversity of cell types that compose this tissue. The immune cells found in the stromal portion of adipose tissue play an important role on the modulation of inflammation by adipocytokines secretion. The interactions between metabolic active tissues and immune cells, called immunometabolism, is an important field for discovering new pathways and approaches to treat immunometabolic diseases, such as obesity and cancer. Moreover, physical exercise is widely known as a tool for prevention and adjuvant treatment on metabolic diseases. More specifically, aerobic exercise training is able to increase the energy expenditure, reduce the nutrition overload and modify the profile of adipocytokines and myokines with paracrine and endocrine effects. Therefore, our aim in this review was to cover the effects of aerobic exercise training on the immunometabolism of adipose tissue in obesity and cancer, focusing on the exercise-related modification on adipose tissue or immune cells isolated as well as their interaction.
Assuntos
Tecido Adiposo/fisiopatologia , Terapia por Exercício , Doenças Metabólicas/prevenção & controle , Neoplasias/prevenção & controle , Obesidade/prevenção & controle , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Animais , Humanos , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/patologiaRESUMO
It is well-known that mitochondrial DNA (mtDNA) can escape to intracellular or extracellular compartments under different stress conditions, yet understanding their escape mechanisms remains a challenge. Although Bax/Bak pores and VDAC oligomers are the strongest possibilities, other mechanisms may be involved. For example, mitochondria permeability transition, altered mitophagy, and mitochondrial dynamics are associated with intracellular mtDNA escape, while extracellular traps and extracellular vesicles can participate in extracellular mtDNA escape. The evidence suggests that mtDNA escape is a complex event with more than one mechanism involved. In addition, once the mtDNA is outside the mitochondria, the effects can be complex. Different danger signal sensors recognize the mtDNA as a damage-associated molecular pattern, triggering an innate immune inflammatory response that can be observed in multiple metabolic diseases characterized by chronic inflammation, including autoimmune diseases, diabetes, cancer, and cardiovascular disorders. For these reasons, we will review the most recent evidence regarding mtDNA escape mechanisms and their impact on different metabolic diseases.
Assuntos
DNA Mitocondrial/genética , Doenças Metabólicas/genética , Mitocôndrias/genética , Estresse Oxidativo/genética , Humanos , Inflamação/genética , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Transdução de Sinais/genéticaRESUMO
Studies in mice undergoing acute Trypanosoma cruzi infection and patients with Chagas disease, led to identify several immune-neuroendocrine disturbances and metabolic disorders. Here, we review relevant findings concerning such abnormalities and discuss their possible influence on disease physiopathology.
Assuntos
Doença de Chagas/imunologia , Doenças Metabólicas/imunologia , Células Neuroendócrinas/imunologia , Trypanosoma cruzi/imunologia , Animais , Doença de Chagas/parasitologia , Humanos , Doenças Metabólicas/parasitologia , Células Neuroendócrinas/parasitologiaRESUMO
Interleukin-6 (IL-6) is a unique cytokine that can play both pro- and anti-inflammatory roles depending on the anatomical site and conditions under which it has been induced. Specific neurons of the hypothalamus provide important signals to control food intake and energy expenditure. In individuals with obesity, a microglia-dependent inflammatory response damages the neural circuits responsible for maintaining whole-body energy homeostasis, resulting in a positive energy balance. However, little is known about the role of IL-6 in the regulation of hypothalamic microglia. In this systematic review, we asked what types of conditions and stimuli could modulate microglial IL-6 expression in murine model. We searched the PubMed and Web of Science databases and analyzed 13 articles that evaluated diverse contexts and study models focused on IL-6 expression and microglia activation, including the effects of stress, hypoxia, infection, neonatal overfeeding and nicotine exposure, lipopolysaccharide stimulus, hormones, exercise protocols, and aging. The results presented in this review emphasized the role of "injury-like" stimuli, under which IL-6 acts as a proinflammatory cytokine, concomitant with marked microglial activation, which drive hypothalamic neuroinflammation. Emerging evidence indicates an important correlation of basal IL-6 levels and microglial function with the maintenance of hypothalamic homeostasis. Advances in our understanding of these different contexts will lead to the development of more specific pharmacological approaches for the management of acute and chronic conditions, like obesity and metabolic diseases, without disturbing the homeostatic functions of IL-6 and microglia in the hypothalamus.
Assuntos
Regulação da Expressão Gênica/imunologia , Hipotálamo/imunologia , Interleucina-6/imunologia , Doenças Metabólicas/imunologia , Microglia/imunologia , Obesidade/imunologia , Animais , Humanos , Hipotálamo/patologia , Doenças Metabólicas/patologia , Camundongos , Microglia/patologia , Obesidade/patologiaRESUMO
Fatty and hydroxycarboxylic acids are one of the main intermediates of energy metabolism in ruminants and critical in the milk production of cattle. High production demands on a dairy farm can induce nutritional imbalances and metabolism disorders, which have been widely associated with the onset of sterile inflammatory processes and increased susceptibility to infections. The literature suggests that short-chain fatty acids (SCFA), long-chain fatty acids (LCFA) and hydroxycarboxylic acids are relevant modulators of the host innate inflammatory response. For instance, increased SCFA and lactate levels are associated with subacute ruminal acidosis (SARA) and the activation of pro-inflammatory processes mediated by diverse leukocyte and vascular endothelial cells. As such, free LCFA and the ketone body ß-hydroxybutyrate are significantly increased in the plasma 1-2 weeks postpartum, coinciding with the time period in which cows are more susceptible to acquiring infectious diseases that the host innate immune system should actively oppose. Today, many of these pro-inflammatory responses can be related to the activation of specific G protein-coupled receptors, including GPR41/FFA3 and GPR43/FFA2 for SCFA; GPR40/FFA1 and GPR120/FFA4 for LCFA, GPR109A/HCA2 for ketone body ß-hydroxybutyrate, and GPR81/HCA1 for lactate, all expressed in different bovine tissues. The activation of these receptors modulates the release of intracellular granules [e.g., metalloproteinase-9 (MMP-9) and lactoferrin], radical oxygen species (ROS) production, chemotaxis, and the production of relevant pro-inflammatory mediators. The article aimed to review the role of natural ligands and receptors and the resulting impact on the host innate immune reaction of cattle and, further, to address the most recent evidence supporting a potential connection to metabolic disorders.
Assuntos
Acidose/veterinária , Ácidos Graxos não Esterificados/imunologia , Imunidade Inata , Doenças Metabólicas/veterinária , Receptores Acoplados a Proteínas G/imunologia , Acidose/metabolismo , Animais , Bovinos/imunologia , Bovinos/metabolismo , Metabolismo Energético , Ácidos Graxos Voláteis/imunologia , Feminino , Inflamação , Lactatos/metabolismo , Doenças Metabólicas/imunologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Due to immunomodulatory properties, vitamin D status has been implicated in several diseases beyond the skeletal disorders. There is evidence that its deficiency deteriorates the gut barrier favoring translocation of endotoxins into the circulation and systemic inflammation. Few studies investigated whether the relationship between vitamin D status and metabolic disorders would be mediated by the gut microbiota composition. OBJECTIVE: We examined the association between vitamin D intake and circulating levels of 25(OH)D with gut microbiota composition, inflammatory markers and biochemical profile in healthy individuals. METHODS: In this cross-sectional analysis, 150 young healthy adults were stratified into tertiles of intake and concentrations of vitamin D and their clinical and inflammatory profiles were compared. The DESeq2 was used for comparisons of microbiota composition and the log2 fold changes (log2FC) represented the comparison against the reference level. The association between 25(OH)D and fecal microbiota (16S rRNA sequencing, V4 region) was tested by multiple linear regression. RESULTS: Vitamin D intake was associated with its concentration (r=0.220, p=0.008). There were no significant differences in clinical and inflammatory variables across tertiles of intake. However, lipopolysaccharides increased with the reduction of 25(OH)D (p-trend <0.05). Prevotella was more abundant (log2FC 1.67, p<0.01), while Haemophilus and Veillonella were less abundant (log2FC -2.92 and -1.46, p<0.01, respectively) in the subset with the highest vitamin D intake (reference) than that observed in the other subset (first plus second tertiles). PCR (r=-0.170, p=0.039), E-selectin (r=-0.220, p=0.007) and abundances of Coprococcus (r=-0.215, p=0.008) and Bifdobacterium (r=-0.269, p=0.001) were inversely correlated with 25(OH)D. After adjusting for age, sex, season and BMI, 25(OH)D maintained inversely associated with Coprococcus (ß=-9.414, p=0.045) and Bifdobacterium (ß=-1.881, p=0.051), but significance disappeared following the addition of inflammatory markers in the regression models. CONCLUSION: The role of vitamin D in the maintenance of immune homeostasis seems to occur in part by interacting with the gut microbiota. The attenuation of association of bacterial genera by inflammatory markers suggests that inflammation participate in part in the relationship between the gut microbiota and vitamin D concentration. Studies with appropriate design are necessary to address hypothesis raised in the current study.
Assuntos
Microbioma Gastrointestinal/imunologia , Fatores Imunológicos/farmacologia , Fatores Imunológicos/fisiologia , Vitamina D/fisiologia , Adulto , Antropometria , Pressão Sanguínea , Estudos Transversais , Dieta , Exercício Físico , Fezes/microbiologia , Feminino , Humanos , Hidroxicolecalciferóis/sangue , Inflamação/sangue , Lipopolissacarídeos/farmacologia , Masculino , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , RNA Ribossômico 16S/análise , Valores de Referência , Vitamina D/sangue , Vitamina D/farmacologia , Vitaminas/farmacologia , Adulto JovemRESUMO
γ-oryzanol (Orz), a steryl ferulate extracted from rice bran layer, exerts a wide spectrum of biological activities. In addition to its antioxidant activity, Orz is often associated with cholesterol-lowering, anti-inflammatory, anti-cancer and anti-diabetic effects. In recent years, the usefulness of Orz has been studied for the treatment of metabolic diseases, as it acts to ameliorate insulin activity, cholesterol metabolism, and associated chronic inflammation. Previous studies have shown the direct action of Orz when downregulating the expression of genes that encode proteins related to adiposity (CCAAT/enhancer binding proteins (C/EBPs)), inflammatory responses (nuclear factor kappa-B (NF-κB)), and metabolic syndrome (peroxisome proliferator-activated receptors (PPARs)). It is likely that this wide range of beneficial activities results from a complex network of interactions and signals triggered, and/or inhibited by its antioxidant properties. This review focuses on the significance of Orz in metabolic disorders, which feature remarkable oxidative imbalance, such as impaired glucose metabolism, obesity, and inflammation.