RESUMEN
Obesity is a known driver of endometrial cancer. In this issue of the JCI, Gómez-Banoy and colleagues investigated a cohort of patients with advanced endometrial cancer treated with immune checkpoint inhibitors targeting the interaction between programmed cell death receptor-1 (PD-1) and its ligand (PD-L1). Notably, a BMI in the overweight or obese range was paradoxically associated with improved progression-free and overall survival. A second paradox emerged from CT analyses of visceral adipose tissue, viewed as an unhealthy fat depot in most other contexts, the quantity of which was also associated with improved treatment outcomes. Though visceral adiposity may have value as a biomarker to inform personalized treatment strategies, of even greater impact would be if a therapeutic strategy emerges from the future identification of adipose-derived mediators of this putative anticancer immune-priming effect.
Asunto(s)
Neoplasias Endometriales , Grasa Intraabdominal , Humanos , Femenino , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/terapia , Neoplasias Endometriales/patología , Neoplasias Endometriales/tratamiento farmacológico , Grasa Intraabdominal/inmunología , Inmunoterapia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Obesidad/inmunología , Obesidad/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
Development of type 2 diabetes mellitus (T2DM) is associated with low-grade chronic type 2 inflammation and disturbance of glucose homeostasis. Group 2 innate lymphoid cells (ILC2s) play a critical role in maintaining adipose homeostasis via the production of type 2 cytokines. Here, we demonstrate that CB2, a G-protein-coupled receptor (GPCR) and member of the endocannabinoid system, is expressed on both visceral adipose tissue (VAT)-derived murine and human ILC2s. Moreover, we utilize a combination of ex vivo and in vivo approaches to explore the functional and therapeutic impacts of CB2 engagement on VAT ILC2s in a T2DM model. Our results show that CB2 stimulation of ILC2s protects against insulin-resistance onset, ameliorates glucose tolerance, and reverses established insulin resistance. Our mechanistic studies reveal that the therapeutic effects of CB2 are mediated through activation of the AKT, ERK1/2, and CREB pathways on ILC2s. The results reveal that the CB2 agonist can serve as a candidate for the prevention and treatment of T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Linfocitos , Receptor Cannabinoide CB2 , Animales , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Receptor Cannabinoide CB2/metabolismo , Receptor Cannabinoide CB2/agonistas , Linfocitos/metabolismo , Linfocitos/inmunología , Linfocitos/efectos de los fármacos , Humanos , Ratones , Masculino , Ratones Endogámicos C57BL , Inmunidad Innata/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/efectos de los fármacos , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunología , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer.
Asunto(s)
Dieta Alta en Grasa , Inflamación , Grasa Intraabdominal , Neutrófilos , Obesidad , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/metabolismo , Animales , Obesidad/microbiología , Obesidad/inmunología , Humanos , Neutrófilos/inmunología , Dieta Alta en Grasa/efectos adversos , Ratones , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Microbioma Gastrointestinal/inmunología , Masculino , Ratones Endogámicos C57BL , Femenino , Heces/microbiología , Microbiota/inmunología , Células TH1/inmunología , Infiltración NeutrófilaRESUMEN
IMPORTANCE: Epicardial adipose tissue (EAT) is a biologically active organ surrounding myocardium and coronary arteries that has been associated with coronary artery disease (CAD) and atrial fibrillation. Previous work has shown that EAT exhibits beige features. OBJECTIVE: Our objective was to determine whether the stromal vascular fraction of the human EAT contains innate or adaptive lymphoid cells compared to thoracic subcutaneous (thSAT), visceral abdominal (VAT) and subcutaneous abdominal (abSAT). PARTICIPANTS: New pangenomic microarray analysis was performed on previous transcriptomic dataset using significance analysis of microarray and ingenuity pathway analysis (n=41) to identify specific immune signature and its link with browning genes. EAT, thSAT, VAT and abSAT samples from explanted patients with severe cardiomyopathies and multi-organ donor patients (n=17) were used for flow cytometry (FC) immunophenotyping assay. Patients were on average 55±16 years-old; 47% had hypertension and 6% CAD. Phenotypic adaptive and innate immune profiles were performed using a TBNK panel and a specific ILC1-2-3 panel including CD127, CD117, CRTH2 (CD294) and activation markers such as CD25 and CD69. RESULTS: Transcriptomic analysis showed a significant positive correlation between the TH2 immune pathway (IL-4, IL-5, IL-13, IL-25, IL-33) and browning genes (UCP-1, PRDM16, TMEM26, CITED1, TBX1) in EAT versus thSAT (R=0.82, P<0.0001). Regarding adaptive immune cells, a preponderance of CD8T cells, a contingent of CD4T cells, and a few B cells were observed in all ATs (P<0.0001). In innate lymphoid cells (ILCs), an increase was observed in visceral ATs (i.e. EAT; VAT 35±8ILCs/g of tissue) compared to their subcutaneous counterpart (i.e. thSAT+abSAT: 8±3 ILCs/g of AT, P=0.002), with a difference in the proportion of the 3 subtypes of ILCs (ILC1>ILC3>ILC2). In addition, we observed an increase in EAT-ILC2 compared to other ATs and almost all these EAT-ILC2 expressed CD69 and/or CD25 activation markers (99.75±0.16%; P<0.0001). We also observed more NKs in EAT and VAT (1520±71 cells/g of AT) than in SATs (562±17 cells/g of AT); P=0.01. CONCLUSION: This is the first study to provide a comparison between innate and adaptive lymphoid cells in human epicardial versus abdominal or thoracic adipose tissues. Further studies are ongoing to decipher whether these cells could be involved in EAT beiging. TRIAL REGISTRATION: CODECOH No. DC-2021-4518 The French agency of biomedicine PFS21-005.
Asunto(s)
Inmunidad Adaptativa , Tejido Adiposo , Inmunidad Innata , Pericardio , Humanos , Pericardio/inmunología , Pericardio/patología , Masculino , Persona de Mediana Edad , Femenino , Tejido Adiposo/inmunología , Anciano , Adulto , Linfocitos/inmunología , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Transcriptoma , Tejido Adiposo EpicárdicoRESUMEN
Fat is stored in distinct depots with unique features in both mice and humans and B cells reside in all adipose depots. We have shown that B cells modulate cardiometabolic disease through activities in two of these key adipose depots: visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT). VAT refers to the adipose tissue surrounding organs, within the abdomen and thorax, and is comprised predominantly of white adipocytes. This depot has been implicated in mediating obesity-related dysmetabolism. PVAT refers to adipose tissue surrounding major arteries. It had long been thought to exist to provide protection and insulation for the vessel, yet recent work demonstrates an important role for PVAT in harboring immune cells, promoting their function and regulating the biology of the underlying vessel. The role of B-2 cells and adaptive immunity in adipose tissue biology has been nicely reviewed elsewhere. Given that, the predominance of B-1 cells in adipose tissue at homeostasis, and the emerging role of B-1 cells in a variety of disease states, we will focus this review on how B-1 cells function in VAT and PVAT depots to promote homeostasis and limit inflammation linked to cardiometabolic disease and factors that regulate this function.
Asunto(s)
Tejido Adiposo , Inmunidad Innata , Inflamación , Humanos , Animales , Inflamación/inmunología , Inflamación/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunología , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Enfermedades Metabólicas/inmunología , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/etiología , InmunomodulaciónRESUMEN
Regulatory T (Treg) cells in epidydimal visceral adipose tissue (eVAT) of lean mice and humans regulate metabolic homeostasis. We found that constitutive or punctual depletion of eVAT-Treg cells reined in the differentiation of stromal adipocyte precursors. Co-culture of these precursors with conditional medium from eVAT-Treg cells limited their differentiation in vitro, suggesting a direct effect. Transcriptional comparison of adipocyte precursors, matured in the presence or absence of the eVAT-Treg-conditioned medium, identified the oncostatin-M (OSM) signaling pathway as a key distinction. Addition of OSM to in vitro cultures blocked the differentiation of adipocyte precursors, while co-addition of anti-OSM antibodies reversed the ability of the eVAT-Treg-conditioned medium to inhibit in vitro adipogenesis. Genetic depletion of OSM (specifically in Treg) cells or of the OSM receptor (specifically on stromal cells) strongly impaired insulin sensitivity and related metabolic indices. Thus, Treg-cell-mediated control of local progenitor cells maintains adipose tissue and metabolic homeostasis, a regulatory axis seemingly conserved in humans.
Asunto(s)
Adipocitos , Diferenciación Celular , Homeostasis , Resistencia a la Insulina , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Humanos , Ratones , Adipocitos/metabolismo , Diferenciación Celular/inmunología , Oncostatina M/metabolismo , Transducción de Señal , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/citología , Grasa Intraabdominal/inmunología , Células del Estroma/metabolismo , Ratones Endogámicos C57BL , Técnicas de Cocultivo , Adipogénesis , Células Cultivadas , Masculino , Tejido Adiposo/metabolismo , Tejido Adiposo/citología , Medios de Cultivo Condicionados/farmacologíaRESUMEN
It is now widely understood that visceral adipose tissue (VAT) is a highly active and dynamic organ, with many functions beyond lipid accumulation and storage. In this review, we discuss the immunological role of this tissue, underpinned by the presence of fat-associated lymphoid clusters (FALCs). FALC's distinctive structure and stromal cell composition support a very different immune cell mix to that found in classical secondary lymphoid organs, which underlies their unique functions of filtration, surveillance, innate-like immune responses, and adaptive immunity within the serous cavities. FALCs are important B cell hubs providing B1 cell-mediated frontline protection against infection and supporting B2 cell-adaptative immune responses. Beyond these beneficial immune responses orchestrated by FALCs, immune cells within VAT play important homeostatic role. Dysregulation of immune cells during obesity and aging leads to chronic pathological "metabolic inflammation", which contributes to the development of cardiometabolic diseases. Here, we examine the emerging and complex functions of B cells in VAT homeostasis and the metabolic complications of obesity, highlighting the potential role that FALCs play and emphasize the areas where further research is needed.
Asunto(s)
Linfocitos B , Homeostasis , Grasa Intraabdominal , Humanos , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Inmunidad AdaptativaRESUMEN
Adipose tissue stores excess energy and produces a broad range of factors that regulate multiple physiological processes including systemic energy homeostasis. Visceral adipose tissue (VAT) plays a particularly important role in glucose metabolism as its endocrine function underpins food uptake and energy expenditure. Caloric excess triggers VAT inflammation which can impair insulin sensitivity and cause metabolic deregulation. Regulatory T cells (Tregs) that reside in the VAT suppress inflammation and protect from metabolic disease. The cellular components of VAT and its secretory products play a vital role in fostering the differentiation and maintenance of VAT Tregs. Critically, the physiology and inflammatory tone of VAT exhibit sex-specific disparities, resulting in substantial VAT Treg heterogeneity. Indeed, cytokines and sex hormones promote the differentiation of distinct populations of mature VAT Tregs, each characterized by unique phenotypes, homeostatic requirements, and functions. This review focuses on key findings that have significantly advanced our understanding of VAT Treg biology and the current state of the field, while also discussing open questions that require further exploration.
Asunto(s)
Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Animales , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/inmunología , Diferenciación Celular , Citocinas/metabolismo , Metabolismo Energético , Transcripción Genética , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunología , Regulación de la Expresión Génica , Hormonas Esteroides Gonadales/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , HomeostasisRESUMEN
Regulatory T cells (Tregs) within the visceral adipose tissue (VAT) play a crucial role in controlling tissue inflammation and maintaining metabolic health. VAT Tregs display a unique transcriptional profile and T cell receptor (TCR) repertoire, and closely interact with adipocytes, stromal cells, and other immune components within the local VAT microenvironment. However, in the context of obesity, there is a notable decline in VAT Tregs, resulting in heightened VAT inflammation and insulin resistance. A comprehensive understanding of the biology of VAT Tregs is essential for the development of Treg-based therapies for mitigating obesity-associated metabolic diseases. Recent advancements in lineage tracing tools, genetic mouse models, and various single cell "omics" techniques have significantly progressed our understandings of the origin, differentiation, and regulation of this unique VAT Treg population at steady state and during obesity. The identification of VAT-Treg precursor cells in the secondary lymphoid organs has also provided important insights into the timing, location, and mechanisms through which VAT Tregs acquire their distinctive phenotype that enables them to function within a lipid-rich microenvironment. In this review, we highlight key recent breakthroughs in the VAT-Treg field while discussing pivotal questions that remain unanswered.
Asunto(s)
Grasa Intraabdominal , Obesidad , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Humanos , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/inmunología , Obesidad/inmunología , Obesidad/metabolismo , Diferenciación CelularRESUMEN
Gestational diabetes mellitus (GDM) is a frequent and serious complication of pregnancy, often associated with obesity. Metabolic dysfunction and metainflammation are evident in both obesity and GDM. In this cross-sectional study, we aimed at defining the direct contribution of the immune system in GDM, across the main metabolic tissues, specifically focussing on elucidating the roles of obesity and GDM to the clinical outcome. Using immunoassays and multicolour flow cytometry, cytokine profiles and immune cell frequencies were measured in maternal circulation and central metabolic tissues [placenta and visceral adipose tissue (VAT)] in GDM-diagnosed (nâ =â 28) and normal glucose tolerant (nâ =â 32) women undergoing caesarean section. Participants were sub-grouped as non-obese [body mass index (BMI)â <â 30 kg/m2] or obese (BMIâ ≥â 30 kg/m2). Unsupervised data analysis was performed on the flow cytometry data set to identify functional alterations. GDM obese participants had significantly elevated circulating IL-6 and IL-17A levels. GDM non-obese participants had elevated circulating IL-12p70, elevated placental IL-17A, and VAT IFN-γ production. Unsupervised clustering of immune populations across the three biological sites simultaneously, identified different NK- and T-cell phenotypes that were altered in NGT obese and GDM non-obese participants, while a classical tissue monocyte cluster was increased in GDM obese participants. In this study, there was significant evidence of subclinical inflammation, and significant alterations in clusters of NK cells, T cells, and tissue monocyte populations in GDM. While increased adiposity assimilates with increased inflammation in the non-pregnant state, this overt relationship may not be as evident during pregnancy and warrants further examination in future longitudinal studies.
Asunto(s)
Diabetes Gestacional , Inflamación , Obesidad , Humanos , Femenino , Embarazo , Diabetes Gestacional/inmunología , Diabetes Gestacional/sangre , Adulto , Obesidad/inmunología , Inflamación/inmunología , Estudios Transversales , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/metabolismo , Placenta/inmunología , Placenta/metabolismo , Células Asesinas Naturales/inmunología , Interleucina-17/sangre , Citocinas/sangre , Citocinas/metabolismo , Interleucina-6/sangre , Índice de Masa Corporal , Linfocitos T/inmunología , Interferón gamma/sangreRESUMEN
Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44hiCD62LlowCD69+) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.
Asunto(s)
Envejecimiento , Inflamación , Grasa Intraabdominal , Subgrupos de Linfocitos T , Animales , Inflamación/inmunología , Interleucina-6/metabolismo , Grasa Intraabdominal/inmunología , Ratones , Obesidad/metabolismo , Subgrupos de Linfocitos T/inmunologíaRESUMEN
CONTEXT: Circulating adiponectin levels are decreased in pregnant women with obesity or gestational diabetes, and this is believed to contribute to the insulin resistance and increased risk of fetal overgrowth associated with these conditions. However, the molecular mechanisms regulating adiponectin secretion from maternal adipose tissues in pregnancy are poorly understood. OBJECTIVE: We tested the hypothesis that obesity in pregnancy is associated with adipose tissue insulin resistance and increased adiponectin ubiquitination and degradation, caused by inflammation and endoplasmic reticulum (ER) stress. METHODS: Visceral adipose tissues were collected from lean and obese pregnant humans and mice. Total and ubiquitinated adiponectin, and markers of inflammation, ER stress, and insulin resistance were examined in adipose tissues. The role of insulin, inflammation, and ER stress in mediating adiponectin ubiquitination and degradation was examined using 3T3L-1 adipocytes. RESULTS: Obesity in pregnancy is associated with adipose tissue inflammation, ER stress, insulin resistance, increased adiponectin ubiquitination, and decreased total abundance of adiponectin. Adiponectin ubiquitination was increased in visceral fat of obese pregnant women as compared to lean pregnant women. We further observed that insulin prevents, whereas ER stress and inflammation promote, adiponectin ubiquitination and degradation in differentiated 3T3-L1 adipocytes. CONCLUSION: We have identified adiponectin ubiquitination as a key mechanism by which obesity diminishes adiponectin secretion in pregnancy. This information will help us better understand the mechanisms controlling maternal insulin resistance and fetal growth in pregnancy and may provide a foundation for the development of strategies aimed at improving adiponectin production in pregnant women with obesity or gestational diabetes.
Asunto(s)
Adiponectina/metabolismo , Diabetes Gestacional/metabolismo , Insulina/metabolismo , Obesidad Materna/metabolismo , Células 3T3-L1 , Adipocitos/metabolismo , Adiponectina/análisis , Adulto , Animales , Estudios de Cohortes , Diabetes Gestacional/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Recién Nacido , Resistencia a la Insulina/inmunología , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/patología , Masculino , Ratones , Obesidad Materna/inmunología , Obesidad Materna/patología , Embarazo , Proteolisis , Ubiquitinación/inmunologíaRESUMEN
CONTEXT: Chronic glucocorticoid (GC) overexposure, resulting from endogenous Cushing's syndrome (CS) or exogenous GC therapy, causes several adverse outcomes, including persistent central fat accumulation associated with a low-grade inflammation. However, no previous multiomics studies in visceral adipose tissue (VAT) from patients exposed to high levels of unsuppressed GC during active CS or after remission are available yet. OBJECTIVE: To determine the persistent VAT transcriptomic alterations and epigenetic fingerprints induced by chronic hypercortisolism. METHODS: We employed a translational approach combining high-throughput data on endogenous CS patients and a reversible CS mouse model. We performed RNA sequencing and chromatin immunoprecipitation sequencing on histone modifications (H3K4me3, H3K27ac, and H3K27me3) to identify persistent transcriptional and epigenetic signatures in VAT produced during active CS and maintained after remission. RESULTS: VAT dysfunction was associated with low-grade proinflammatory status, macrophage infiltration, and extracellular matrix remodeling. Most notably, chronic hypercortisolism caused a persistent circadian rhythm disruption in VAT through core clock genes modulation. Importantly, changes in the levels of 2 histone modifications associated to gene transcriptional activation (H3K4me3 and H3K27ac) correlated with the observed differences in gene expression during active CS and after CS remission. CONCLUSION: We identified for the first time the persistent transcriptional and epigenetic signatures induced by hypercortisolism in VAT, providing a novel integrated view of molecular components driving the long-term VAT impairment associated with CS.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/complicaciones , Síndrome de Cushing/metabolismo , Glucocorticoides/efectos adversos , Grasa Intraabdominal/inmunología , Obesidad Abdominal/genética , Administración Oral , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/inmunología , Neoplasias de las Glándulas Suprarrenales/orina , Adulto , Animales , Biopsia , Secuenciación de Inmunoprecipitación de Cromatina , Corticosterona/administración & dosificación , Corticosterona/efectos adversos , Estudios Transversales , Síndrome de Cushing/inmunología , Síndrome de Cushing/patología , Modelos Animales de Enfermedad , Epigenoma/efectos de los fármacos , Epigenoma/inmunología , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/metabolismo , Humanos , Hidrocortisona/metabolismo , Hidrocortisona/orina , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/metabolismo , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Masculino , Ratones , Persona de Mediana Edad , Obesidad Abdominal/inmunología , Obesidad Abdominal/patología , RNA-Seq , Transcriptoma/efectos de los fármacos , Transcriptoma/inmunologíaRESUMEN
Type 1 diabetes (T1D) is a proinflammatory pathology that leads to the specific destruction of insulin producing ß-cells and hyperglycaemia. Much of the knowledge about type 1 diabetes (T1D) has focused on mechanisms of disease progression such as adaptive immune cells and the cytokines that control their function, whereas mechanisms linked with the initiation of the disease remain unknown. It has been hypothesized that in addition to genetics, environmental factors play a pivotal role in triggering ß-cell autoimmunity. The BioBreeding Diabetes Resistant (BBDR) and LEW1.WR1 rats have been used to decipher the mechanisms that lead to virus-induced T1D. Both animals develop ß-cell inflammation and hyperglycemia upon infection with the parvovirus Kilham Rat Virus (KRV). Our earlier in vitro and in vivo studies indicated that KRV-induced innate immune upregulation early in the disease course plays a causal role in triggering ß-cell inflammation and destruction. Furthermore, we recently found for the first time that infection with KRV induces inflammation in visceral adipose tissue (VAT) detectable as early as day 1 post-infection prior to insulitis and hyperglycemia. The proinflammatory response in VAT is associated with macrophage recruitment, proinflammatory cytokine and chemokine upregulation, endoplasmic reticulum (ER) and oxidative stress responses, apoptosis, and downregulation of adipokines and molecules that mediate insulin signaling. Downregulation of inflammation suppresses VAT inflammation and T1D development. These observations are strikingly reminiscent of data from obesity and type 2 diabetes (T2D) in which VAT inflammation is believed to play a causal role in disease mechanisms. We propose that VAT inflammation and dysfunction may be linked with the mechanism of T1D progression.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/virología , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/virología , Infecciones por Parvoviridae/inmunología , Animales , Humanos , Parvovirus/inmunología , RatasRESUMEN
Arising incidence of metabolic disorders and related diseases caused by obesity is a global health concern. Elucidating the role of the immune system in this process will help to understand the related mechanisms and develop treatment strategies. Here, we have focused on innate immune cells in visceral adipose tissue (VAT) and summarized the roles of these cells in maintaining the homeostasis of VAT. Furthermore, this review reveals the importance of quantitative and functional changes of innate immune cells when the metabolic microenvironment changes due to obesity or excess lipids, and confirms that these changes eventually lead to the occurrence of chronic inflammation and metabolic diseases of VAT. Two perspectives are reviewed, which include sequential changes in various innate immune cells in the steady state of VAT and its imbalance during obesity. Cross-sectional interactions between various innate immune cells at the same time point are also reviewed. Through delineation of a comprehensive perspective of VAT homeostasis in obesity-induced chronic inflammation, and ultimately metabolic dysfunction and disease, we expect to clarify the complex interactive networks among distinct cell populations and propose that these interactions should be taken into account in the development of biotherapeutic strategies.
Asunto(s)
Homeostasis/inmunología , Inmunidad Innata/inmunología , Grasa Intraabdominal/inmunología , Obesidad/inmunología , Animales , HumanosRESUMEN
Both obesity and aging are associated with the development of metabolic diseases such as type 2 diabetes and cardiovascular disease. Chronic low-grade inflammation of adipose tissue is one of the mechanisms implicated in the progression of these diseases. Obesity and aging trigger adipose tissue alterations that ultimately lead to a pro-inflammatory phenotype of the adipose tissue-resident immune cells. Obesity and aging also share other features such as a higher visceral vs. subcutaneous adipose tissue ratio and a decreased lifespan. Here, we review the common characteristics of obesity and aging and the alterations in white adipose tissue and resident immune cells. We focus on the adipose tissue metabolic derangements in obesity and aging such as inflammation and adipose tissue remodeling.
Asunto(s)
Adipocitos Blancos/inmunología , Tejido Adiposo Blanco/inmunología , Envejecimiento/inmunología , Distribución de la Grasa Corporal/métodos , Obesidad/inmunología , Adipocitos Blancos/metabolismo , Adipocitos Blancos/patología , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Humanos , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Obesidad/metabolismo , Obesidad/patologíaRESUMEN
Background and aims: Group 2 innate lymphoid cells (ILC2s) have been implicated in the regulation of metabolic homeostasis in mice. Methods: In this study, the role of ILC2s in white adipose tissue (WAT) was investigated using ST2, an IL-33 receptor that is expressed on ILC2 knockout mice. Results: The deficiency of ST2 decreased ILC2s in WAT, whereas ex-ILC2, which acquired group 1 innate lymphoid cell (ILC1)-like traits, was increased. This led to significant metabolic disorders such as visceral fat obesity, decreased browning in WAT, reduction of energy metabolism, and impaired glucose tolerance, compared to wild type (WT) mice. Those metabolic abnormalities of ST2-knockout (ST2KO) mice were not ameliorated by IL-33 administration, but impaired glucose tolerance and visceral fat obesity were significantly improved by transplantation of ILCs from the bone marrow of WT mice. The relative expression of Cd36 in WAT increased due to the deficiency of ST2, and the storage of saturated fatty acids in WAT of ST2KO mice was significantly higher than that of WT mice. Moreover, saturated fatty acids aggravated the chronic inflammation in adipocytes, promoted the differentiation of M1-like macrophages, and inhibited that of M2-like macrophages. Conclusions: Our results indicated that ILC2 regulates diet-induced obesity and chronic inflammation through the regulation of saturated fatty acid absorption in visceral adipose tissue.
Asunto(s)
Glucemia/metabolismo , Ácidos Grasos/metabolismo , Intolerancia a la Glucosa/metabolismo , Inmunidad Innata , Resistencia a la Insulina , Grasa Intraabdominal/metabolismo , Linfocitos/metabolismo , Absorción Fisiológica , Traslado Adoptivo , Animales , Glucemia/efectos de los fármacos , Antígenos CD36/metabolismo , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/inmunología , Homeostasis , Inmunidad Innata/efectos de los fármacos , Inflamación/inmunología , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/genética , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/farmacología , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/inmunología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/inmunología , Obesidad/metabolismo , Células RAW 264.7RESUMEN
3,5-diiodo-thyronine (T2), an endogenous metabolite of thyroid hormones, exerts beneficial metabolic effects. When administered to overweight rats receiving a high fat diet (HFD), it significantly reduces body fat accumulation, which is a risk factor for the development of an inflammatory state and of related metabolic diseases. In the present study, we focused our attention on T2 actions aimed at improving the adverse effects of long-lasting HFD such as the adipocyte inflammatory response. For this purpose, three groups of rats were used throughout: i) receiving a standard diet for 14 weeks; ii) receiving a HFD for 14 weeks, and iii) receiving a HFD for 14 weeks with a simultaneous daily injection of T2 for the last 4 weeks. The results showed that T2 administration ameliorated the expression profiles of pro- and anti-inflammatory cytokines, reduced macrophage infiltration in white adipose tissue, influenced their polarization and reduced lymphocytes recruitment. Moreover, T2 improved the expression of hypoxia markers, all altered in HFD rats, and reduced angiogenesis by decreasing the pro-angiogenic miR126 expression. Additionally, T2 reduced the oxidative damage of DNA, known to be associated to the inflammatory status. This study demonstrates that T2 is able to counteract some adverse effects caused by a long-lasting HFD and to produce beneficial effects on inflammation. Irisin and SIRT1 pathway may represent a mechanism underlying the above described effects.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Diyodotironinas/farmacología , Hipoxia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Grasa Intraabdominal/efectos de los fármacos , Macrófagos/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Adipoquinas/metabolismo , Animales , Daño del ADN , Hipoxia/metabolismo , Hipoxia/patología , Inflamación/etiología , Inflamación/patología , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/metabolismo , Macrófagos/inmunología , Masculino , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Sobrepeso/fisiopatología , Estrés Oxidativo , Ratas , Ratas WistarRESUMEN
Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPRdn , hIAPP and PNPLA3I148M . Transgenic effect increased the risk of metabolic disorders. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Molecular pathways related to CD8+ T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs' liver samples. We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Taken together, this study provides a valuable large animal model for the clinical study of metaflammation and metabolic diseases.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diabetes Mellitus Tipo 2/inmunología , Grasa Intraabdominal/inmunología , Hígado/inmunología , Activación de Linfocitos , Enfermedad del Hígado Graso no Alcohólico/inmunología , Precursor de Proteína beta-Amiloide/genética , Animales , Animales Modificados Genéticamente , Glucemia/metabolismo , Linfocitos T CD8-positivos/metabolismo , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Lipasa/genética , Lípidos/sangre , Hígado/metabolismo , Hígado/patología , Masculino , Proteínas de la Membrana/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Receptores de la Hormona Gastrointestinal/genética , Porcinos/genética , TranscriptomaRESUMEN
The anti-inflammatory adipokine CTRP-3 might affect innate immune reactions such as NOD1. The impact of CTRP-3 on NOD1-mediated inflammation in adipocytes and monocytic cells as well as on NOD1 expression was investigated. Murine 3T3-L1 pre-adipocytes and adipocytes as well as human THP-1 monocyte-like cells were co-stimulated with the synthetic NOD1 agonist Tri-DAP and recombinant CTRP-3. Gonadal adipose tissue and primary adipocytes were obtained from a murine model carrying a knockout (KO) of CTRP-3 in adipocytes but not in stroma-vascular cells. Wildtype mice with lipopolysaccharide (LPS)-induced elevated NOD1 expression were treated with CTRP-3. Secreted inflammatory cytokines in cell supernatants were measured by ELISA and mRNA levels were quantified by RT-PCR. Pro-inflammatory chemokine and cytokine secretion (MCP-1, RANTES, TNFα) was induced by NOD1 activation in adipocytes and monocyte-like cells, and MCP-1 and RANTES release was effectively inhibited by pre-incubation of cells with CTRP-3. CTRP-3 also antagonized LPS-triggered induction of NOD1 gene expression in murine adipose tissue, whereas adipocyte CTRP-3 deficiency upregulated NOD1 expression in adipose tissue. CTRP-3 is an effective antagonist of peptidoglycan-induced, NOD1-mediated inflammation and of LPS-induced NOD1 expression. Since basal NOD1 expression is increased by adipocyte CTRP-3 deficiency, there have to be also inflammation-independent mechanisms of NOD1 expression regulation by CTRP-3.