RESUMEN
OBJECTIVE: To investigate the predictors of response to intravesical Bacillus Calmette-Guerin (BCG) immunotherapy for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) patients. MATERIALS AND METHODS: We retrospectively analyzed the clinicopathological data of 184 intermediate and high risk NMIBC cases receiving transurethral resection of bladder tumor (TURBT) and intravesical BCG immunotherapy from December 2014 to April 2021 at our center. All patients were divided into BCG responders and non-responders. Multivariate Logistic regression analysis was performed to identify the independent predictors of response to intravesical BCG immunotherapy. Univariate and multivariate Cox regression analyses were applied to explore the independent prognostic factors of recurrence-free survival (RFS). Receiver operating characteristic (ROC) curve and Kaplan-Meier survival analysis were also utilized. RESULTS: The RFS of BCG responders was significantly increased compared with BCG non-responders. Multivariate Cox regression analysis demonstrated that low grade, pTa stage, non-CIS, lower relative visceral fat area (rVFA) and lower systemic immune inflammation index (SII) were independent prognostic factors of increased RFS after intravesical BCG immunotherapy. Multivariate Logistic regression analysis demonstrated that pTa stage, low grade, non-CIS, low rVFA, and low SII were independent predictors of response to intravesical BCG immunotherapy. Kaplan-Meier survival analysis indicated that the RFS of patients in low rVFA group or low SII group was significantly increased in comparison with those in high rVFA group or high SII group. ROC curve analysis showed that the area under ROC (AUC) of including SII and rVFA was significantly increased, indicating that the inclusion of preoperative SII and rVFA could significantly improve the predictive efficiency. CONCLUSIONS: Low grade, pTa stage, non-CIS, preoperative lower rVFA and lower SII were vital independent predictors of response to intravesical BCG immunotherapy and were associated with preferable prognosis in NMIBC patients. The inclusion of preoperative SII and rVFA could significantly improve the predictive efficiency.
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Adyuvantes Inmunológicos/uso terapéutico , Vacuna BCG/uso terapéutico , Inmunoterapia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Grasa Abdominal/inmunología , Administración Intravesical , Anciano , Femenino , Humanos , Inflamación/inmunología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/inmunología , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OBJECTIVE: To study the relationship between circulating chemokine cysteine-cysteine motif ligand (CCL) 5 levels and cysteine-cysteine chemokine receptor type 5 (CCR5) expression in peripheral blood mononuclear cells (PBMCs) and adipose tissue with hyperandrogenism and insulin resistance in patients with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: University teaching hospital. PATIENT(S): Fifteen women with PCOS and 15 controls matched for body mass index and age were enrolled in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Plasma levels of CCL3, CCL4, and CCL5 were determined using enzyme-linked immunosorbent assay kits, and omental adipose tissue and PBMCs were analyzed using real-time polymerase chain reaction to determine the expression level of CCR5 in participants. RESULT(S): Levels of CCL5 were significantly higher in women with PCOS. Expression of CCR5 in adipose tissue and PBMCs was significantly higher in women with PCOS compared with that in women in the control group. Cysteine-cysteine chemokine receptor type 5 expression also was upregulated in THP-1 cells after chronic exposure to testosterone. Levels of CCL5 had a significant positive correlation with testosterone levels in women with PCOS. Moreover, CCR5 showed a positive correlation with fasting glucose levels, homeostasis model insulin resistance index, and C-reactive protein. CONCLUSION(S): Increased levels of CCL5 and overexpression of CCR5 in PBMCs and adipose tissue are associated with hyperandrogenism and insulin resistance in women with PCOS. Additionally, CCR5 and CCL5 may be used as biomarkers in the pathogenesis of PCOS.
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Grasa Abdominal/metabolismo , Quimiocina CCL5/metabolismo , Hiperandrogenismo/metabolismo , Resistencia a la Insulina , Leucocitos Mononucleares/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Receptores CCR5/metabolismo , Linfocitos T/metabolismo , Testosterona/sangre , Grasa Abdominal/inmunología , Grasa Abdominal/fisiopatología , Adulto , Glucemia/metabolismo , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Femenino , Humanos , Hiperandrogenismo/diagnóstico , Hiperandrogenismo/inmunología , Hiperandrogenismo/fisiopatología , Insulina/sangre , Leucocitos Mononucleares/inmunología , Activación de Linfocitos , Epiplón , Síndrome del Ovario Poliquístico/diagnóstico , Síndrome del Ovario Poliquístico/inmunología , Síndrome del Ovario Poliquístico/fisiopatología , Receptores CCR5/genética , Linfocitos T/inmunología , Células THP-1 , Regulación hacia Arriba , Adulto JovenRESUMEN
Although not typical lymphoid organs, analysis of the visceral adipose-associated lymphoid tissues has recently substantially expanded our knowledge about the immunological features of these elusive compartments. Recent data have highlighted their considerable complexity in cellular organization and interactions in several biological processes, including adaptive immune responses, tissue plasticity to accommodate mesenchymal stem cells and progenitors, and providing a suitable microenvironment for serosal tumor propagation. This review aims to present a comprehensive view of the adipose-associated lymphoid tissues in local and systemic immune responsiveness, with particular emphasis on the omental and mesenteric lymphoid tissues in the serosal defense of abdominal organs.
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Grasa Abdominal/inmunología , Inmunidad Adaptativa , Tejido Linfoide/inmunología , Membrana Serosa/inmunología , Grasa Abdominal/metabolismo , Adipocitos/inmunología , Adipocitos/metabolismo , Animales , Comunicación Celular , Humanos , Tejido Linfoide/metabolismo , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Células Mieloides/inmunología , Células Mieloides/metabolismo , Neoplasias Peritoneales/inmunología , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/patología , Fenotipo , Membrana Serosa/metabolismoRESUMEN
Thymic stromal lymphopoietin (TSLP) is a cytokine that is known to play a role in inflammatory conditions, especially asthma and atopic dermatitis. It is also recognized to be expressed in human adipose tissue. TSLP production from human adipocytes is stimulated by thyroid-stimulating hormone (TSH). This study aimed to identify TSH-dependent signaling routes that regulate TSLP, to determine if TSLP production is stimulated by other cytokines (IL-1ß and TNF-α), and to examine if TSLP production depends on the adipose depot. Human abdominal differentiated adipocytes were stimulated with TSH, IL-1ß, or TNF-α. Activation of cell signaling kinases was measured by phospho-immunoblot analysis, and TSLP in medium was assessed by ELISA. TSLP responses from abdominal subcutaneous and omental adipocytes were compared. TSH-stimulated TSLP secretion from subcutaneous adipocytes was enhanced by IBMX (raises cAMP levels) and was blocked by UO126 (inhibitor of MEK1/2-ERK1/2). TSLP secretion was stimulated by IL-1ß and by TNF-α. SC-514 (inhibitor of IKKß/NF-κB) only reduced the former. There was no effect of SB203580 (p38 MAPK inhibitor) or SP600125 (JNK inhibitor) on the stimulation by TSH, IL-1ß or TNF-α. Interferon-γ inhibited TSLP responses to TSH, IL-1ß, and TNF-α; IL-4 only blocked the response to TNFα. Intra-abdominal omental adipocytes also release TSLP in response to TSH, IL-1ß, and TNF-α. We conclude TSLP is produced by human differentiated adipocytes derived from subcutaneous or omental depots in response to a variety of agonists. Further studies will be needed to understand what role it may play in adipose biology.
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Grasa Abdominal/inmunología , Adipocitos/inmunología , Citocinas/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Femenino , Humanos , Interleucina-1beta/inmunología , Interleucina-4/inmunología , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Growth hormone (GH) excess in bovine (b)GH transgenic mice has been shown to alter white adipose tissue (WAT) immune cell populations. The present study aimed to evaluate the effects of GH resistance on WAT immune cell populations using GH receptor knockout (GHR-/- ) mice. Eight- and 24-month-old, male GHR-/- and wild-type mice were used. Body composition and tissue weights were determined, and systemic inflammation was assessed by measuring serum cytokine levels. The stromal vascular fraction (SVF) was isolated from three distinct WAT depots, and immune cell populations were quantified using flow cytometry. GHR-/- mice at both ages had decreased body weight but were obese. Although no significant changes were observed in serum levels of the measured cytokines, SVF cell alterations were seen and differed from depot to depot. Total SVF cells were decreased in epidydimal (Epi) depots, whereas SVF cells per gram adipose tissue weight were increased in mesenteric (Mes) depots of GHR-/- mice relative to controls. T cells and T helper cells were increased in Mes at 8 months old, whereas cytotoxic T cells were decreased in subcutaneous (SubQ) at 24 months old. Other cells were unchanged at both ages measured. The present study demonstrates that removal of GH action results in modest and depot-specific changes to several immune cell populations in WAT of intra-abdominal depots (Epi and Mes), which are somewhat surprising results because the SubQ has the largest change in size, whereas the Mes has no size change. Taken together with previous results from bovine GH transgenic mice, these data suggest that GH induces changes in the immune cell population of WAT in a depot-specific manner. Notably, GHR-/- mice appear to be protected from age-related WAT inflammation and immune cell infiltration despite obesity.
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Tejido Adiposo Blanco/patología , Proteínas Portadoras/genética , Inflamación/genética , Inflamación/patología , Obesidad/genética , Obesidad/patología , Grasa Abdominal/inmunología , Grasa Abdominal/patología , Tejido Adiposo Blanco/inmunología , Envejecimiento , Animales , Composición Corporal , Citocinas/sangre , Epidídimo/patología , Hormona del Crecimiento/genética , Hormona del Crecimiento/metabolismo , Inmunidad Celular/genética , Inmunidad Celular/inmunología , Inflamación/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Obesidad/inmunología , Tamaño de los Órganos , Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
The formation of tertiary lymphoid organs (TLOs) is orchestrated by the stromal cells of tissues chronically submitted to inflammatory stimuli, in order to uphold specific adaptive immune responses. We have recently shown that the smooth muscle cells of the arterial wall orchestrate the formation of the TLOs associated with atherosclerosis in response to the local release of TNF-α. Observational studies have recently documented the presence of structures resembling TLOs the creeping fat that develops in the mesentery of patients with Crohn's disease (CD), an inflammatory condition combining a complex and as yet not elucidated infectious and autoimmune responses. We have performed a comprehensive analysis of the TLO structures in order to decipher the mechanism leading to their formation in the mesentery of CD patients, and assessed the effect of infectious and/or inflammatory inducers on the potential TLO-organizer functions of adipocytes. Quantitative analysis showed that both T and B memory cells, as well as plasma cells, are enriched in the CD-affected mesentery, as compared with tissue from control subjects. Immunohistochemistry revealed that these cells are concentrated within the creeping fat of CD patients, in the vicinity of transmural lesions; that T and B cells are compartmentalized in clearly distinct areas; that they are supplied by post-capillary high endothelial venules and drained by lymphatic vessels indicating that these nodules are fully mature TLOs. Organ culture showed that mesenteric tissue samples from CD patients contained greater amounts of adipocyte-derived chemokines and the use of the conditioned medium from these cultures in functional assays was able to actively recruit T and B lymphocytes. Finally, the production of chemokines involved in TLO formation by 3T3-L1 adipocytes was directly elicited by a combination of TNF-α and LPS in vitro. We therefore propose a mechanism in which mesenteric adipocyte, through their production of key chemokines in response to inflammatory/bacterial stimuli, may orchestrate the formation of functional TLOs developing in CD-affected mesentery.
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Grasa Abdominal/inmunología , Quimiocinas/metabolismo , Enfermedad de Crohn/inmunología , Intestinos/patología , Linfocitos/inmunología , Mesenterio/patología , Estructuras Linfoides Terciarias/inmunología , Grasa Abdominal/patología , Adipocitos , Células Cultivadas , Quimiocinas/genética , Estudios de Cohortes , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Larva Migrans , Estudios Prospectivos , Estructuras Linfoides Terciarias/patologíaRESUMEN
IL-15 is a proinflammatory cytokine that plays an essential role in the development and activation of natural killer (NK) cells. Adipose tissue acts as an endocrine organ that secretes cytokines and is an important reservoir for lymphocytes. We hypothesized that activation of the IL-15 signaling in adipose tissue will activate and expand the NK cell population and control tumor growth. We recently developed an adipocyte-targeting recombinant adeno-associated viral (rAAV) vector with minimal off-target transgene expression in the liver. Here, we used this rAAV system to deliver an IL-15/IL-15Rα complex to the abdominal fat by intraperitoneal (i.p.) injection. Adipose IL-15/IL-15Rα complex gene transfer led to the expansion of NK cells in the adipose tissue and spleen in normal mice without notable side effects. The i.p. injection of rAAV-IL-15/IL-15Rα complex significantly suppressed the growth of Lewis lung carcinoma implanted subcutaneously and exerted a significant survival advantage in a B16-F10 melanoma metastasis model. The antitumor effects were associated with the expansion of the NK cells in the blood, spleen, abdominal fat, and tumor, as well as the enhancement of NK cell maturity. Our proof-of-concept preclinical studies demonstrate the safety and efficacy of the adipocyte-specific IL-15/IL-15Rα complex vector as a novel cancer immune gene therapy.
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Terapia Genética , Subunidad alfa del Receptor de Interleucina-15/genética , Interleucina-15/farmacología , Neoplasias/terapia , Grasa Abdominal/efectos de los fármacos , Grasa Abdominal/inmunología , Adipocitos/efectos de los fármacos , Adipocitos/inmunología , Adipocitos/metabolismo , Animales , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/inmunología , Carcinoma Pulmonar de Lewis/terapia , Proliferación Celular/genética , Dependovirus , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Vectores Genéticos/farmacología , Humanos , Interleucina-15/genética , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/patología , Melanoma Experimental/genética , Melanoma Experimental/terapia , Ratones , Metástasis de la Neoplasia , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Transducción de Señal/genéticaRESUMEN
The prevalence of cardiovascular disease has increased among middle-aged women in the United States, yet has declined in middle-aged men. In experimental stroke, middle-aged females have larger strokes and greater inflammation than age-matched males or younger females. The mechanism underlying this shift from an "ischemia-protected" to an "ischemia-sensitive" phenotype in aging females is unknown. One potential factor is an age-related increase in systemic factors that induce inflammation. Increased abdominal fat deposition is seen in women during middle age. Adipose tissue plays a key role in obesity-induced systemic inflammation, including increased pro-inflammatory cytokines. We hypothesized that age and sex differences in adipose immune cells promote an augmented pro-inflammatory milieu in middle-aged females driven by a balance shift between pro-inflammatory and anti-inflammatory T cells. Abdominal adipose tissue immune cells from young (3-4 months) and middle-aged (15-16 months) male and female C57BL/6J mice were analyzed by flow cytometry. Plasma triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were determined with colorimetric assays. Middle-aged mice had higher adipose tissue mass compared to young mice. Lipid profiling showed no sex differences in TG and LDL, but middle-aged females had lower HDL (0.84 ± 0.07 µg/µl) than middle-aged males (1.35 ± 0.06 µg/µl). Flow cytometry data demonstrated an age-associated increase in adipose tissue CD8+ T cells that was augmented by female sex, with middle-aged females having a higher percentage of CD8+ cells (34.4 ± 3.2% of CD3+ T cells) than middle-aged males (24.4 ± 2.2%). This increase in CD8+ T-cell proportion was adipose tissue-specific, as this change was not observed in blood. Middle-aged females had higher numbers of activated (CD69+) CD8+ T cells than males. In addition, female CD8+ T cells produced higher levels of IFN-γ, TNF-α, and granzyme B ex vivo, and females had higher adipose levels of IFN-γ, RANTES and MIP-1ß than middle-aged males. In parallel, females had lower levels of regulatory T cells (Tregs), an anti-inflammatory T-cell subtype, compared to age-matched males. In conclusion, middle-aged females have a detrimental combination of elevated pro-inflammatory T cells and decreased anti-inflammatory Tregs in adipose tissue, which may promote a pro-inflammatory milieu and contribute to increased cardiovascular disease burden in aging females.
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Grasa Abdominal/inmunología , Tejido Adiposo/inmunología , Envejecimiento/fisiología , Linfocitos T CD8-positivos/inmunología , Enfermedades Cardiovasculares/inmunología , Factores Sexuales , Linfocitos T Reguladores/inmunología , Animales , Femenino , Granzimas/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Interferón gamma/metabolismo , Lipoproteínas HDL/metabolismo , Activación de Linfocitos , Masculino , Ratones , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Autologous fat transplantation has been applied widely in clinic. However, the low survival rate is still a problem to be solved. Studies shows that the human adipose-derived stem cells (ADSCs) transfected by vascular endothelial growth factor (VEGF) can improve the survival rate of autologous fat transplantation. Our study is to evaluate the effects of the conditioned medium of VEGF-transfected human adipose-derived stem cells (VEGF-ADSCs-CM) on fat transplantation. ADSCs were isolated and transfected with MOI = 40. The study was divided into three groups, VEGF-ADSCs-CM group, normal-ADSCs-CM group and control group. The conditioned media for VEGF-ADSCs-CM group and normal-ADSCs-CM group were collected, and then mixed with fat, with the mixtures being injected into the back of nude mice. On 4, 7, 15, 30, 60 days after transplantation, the grafts were evaluated on the wet weight, histology, ELISA and western blot. As the results revealed, the survival rate of VEGF-ADSCs-CM group was highest with the best fat cell morphology, and the VEGF secretion of VEGF-ADSCs-CM group was also highest. Therefore, our study demonstrates that VEGF-ADSCs-CM can improve the survival rate of fat transplantation effectively, and VEGF-ADSCs-CM can be regarded as an effective assisted method for fat transplantation.
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Medios de Cultivo Condicionados/farmacología , Supervivencia de Injerto , Trasplante de Células Madre/métodos , Factor A de Crecimiento Endotelial Vascular/genética , Grasa Abdominal/citología , Grasa Abdominal/inmunología , Grasa Abdominal/metabolismo , Grasa Abdominal/cirugía , Adipocitos/citología , Adipocitos/inmunología , Adipocitos/metabolismo , Animales , Diferenciación Celular , Femenino , Expresión Génica , Humanos , Ratones , Ratones Desnudos , Plásmidos/química , Plásmidos/metabolismo , Células Madre/citología , Células Madre/inmunología , Células Madre/metabolismo , Transfección , Trasplante Heterólogo , Factor A de Crecimiento Endotelial Vascular/inmunología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Abdominal fat has been recognized as the most hormonally active tissue secreting a variety of adipocytokines and, therefore, potentially contributing to inflammation. The conicity index (Cindex) has been considered a valuable indicator of central obesity. This study aims to relate plasma concentrations of leptin, adiponectin, interleukin-6 (IL-6), and serum C-reactive protein (CRP) with Cindex values in hemodialysis (HD) patients. Cross-sectional study in 45 HD patients (55.6 % men; DM 20 %; mean age, 68.1 year). Cindex and nutritional-inflammatory markers were used for the abdominal fat depot assessment. Patients were classified as having a low or high median Cindex (MCindex): low group (men, <1.39; women, <1.33) and high group (men, ≥1.39; women, ≥1.33). A combination of plasma leptin, IL-6, adiponectin, and CRP was used to design an inflammatory index (Iindex) while a protein-energy wasting index (PEWindex) was calculated from the Iindex plus the malnutrition-inflammation score (MIS). Waist circumference (WC) and Cindex but not BMI were significantly higher in men than in women (p < 0.01). The MCindex was significantly associated with the adipocytokine profile (CRP, leptin, and adiponectin). Patients with a high MCindex had a higher Iindex and PEWindex (p < 0.01). ROC curve analyses measured by area under the curve (AUC) were 0.69 and 0.68 (p < 0.05), for the Cindex and MCindex, respectively, demonstrating the usefulness of the Cindex as an abdominal fat mass biomarker able for wasting-inflamed HD patients. These findings in HD patients underscore the importance of incorporating the evaluation of one abdominal fat indicator, such as the Cindex and an inflammatory biomarker such as the IL-6 and CRP, in substitution of the BMI, in current clinical practice.
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Adipoquinas/sangre , Adiposidad , Obesidad Abdominal/diagnóstico , Desnutrición Proteico-Calórica/diagnóstico , Diálisis Renal/efectos adversos , Insuficiencia Renal Crónica/terapia , Grasa Abdominal/inmunología , Grasa Abdominal/metabolismo , Adipoquinas/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Índice de Masa Corporal , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Estudios Transversales , Femenino , Humanos , Interleucina-6/sangre , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Evaluación Nutricional , Obesidad Abdominal/complicaciones , Obesidad Abdominal/inmunología , Obesidad Abdominal/metabolismo , Desnutrición Proteico-Calórica/complicaciones , Desnutrición Proteico-Calórica/inmunología , Desnutrición Proteico-Calórica/metabolismo , Insuficiencia Renal Crónica/complicaciones , Sensibilidad y Especificidad , Caracteres Sexuales , Circunferencia de la CinturaAsunto(s)
Grasa Abdominal/metabolismo , Adipoquinas/metabolismo , Inflamación/metabolismo , Síndrome Metabólico/metabolismo , Obesidad/metabolismo , Osteoartritis/metabolismo , Sinovitis/metabolismo , Grasa Abdominal/inmunología , Adipoquinas/inmunología , Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Humanos , Inflamación/epidemiología , Inflamación/inmunología , Síndrome Metabólico/epidemiología , Síndrome Metabólico/inmunología , Obesidad/epidemiología , Obesidad/inmunología , Osteoartritis/epidemiología , Osteoartritis/inmunología , Estrés Mecánico , Sinovitis/inmunología , Soporte de PesoRESUMEN
We have previously described the development of substantial, but reversible obesity in Wistar rats fed with palatable liquid nutrition (Fresubin). In this study, we investigated changes in serum hormone levels, glycemia, fat mass, adipocyte size, and gene expression of adipokines and inflammatory markers in adipose tissue of Wistar rats fed by Fresubin (i) for 5 months, (ii) up to 90 days of age, or (iii) after 90 days of age to characterize metabolic alterations and their reversibility in rats fed with Fresubin. An intra-peritoneal glucose tolerance test was also performed to determine levels of serum leptin, adiponectin, insulin, and C-peptide in 2- and 4-month-old animals. In addition, mesenteric and epididymal adipose tissue weight, adipocyte diameter, and gene expression of pro- and anti-inflammatory adipokines and other markers were determined at the end of the study. Chronic Fresubin intake significantly increased adipocyte diameter, reduced glucose tolerance, and increased serum leptin, adiponectin, insulin, and C-peptide levels. Moreover, gene expression of leptin, adiponectin, CD68, and nuclear factor kappa B was significantly increased in mesenteric adipose tissue of Fresubin fed rats. Monocyte chemotactic protein 1 messenger RNA (mRNA) levels increased in mesenteric adipose tissue only in the group fed Fresubin during the entire experiment. In epididymal adipose tissue, fatty acid binding protein 4 mRNA levels were significantly increased in rats fed by Fresubin during adulthood. In conclusion, chronic Fresubin intake induced complex metabolic alterations in Wistar rats characteristic of metabolic syndrome. However, transition of rats from Fresubin to standard diet reversed these alterations.
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Grasa Abdominal/metabolismo , Adiposidad , Proteínas en la Dieta/efectos adversos , Alimentos Formulados/efectos adversos , Regulación del Desarrollo de la Expresión Génica , Síndrome Metabólico/etiología , Obesidad/etiología , Grasa Abdominal/inmunología , Grasa Abdominal/patología , Adipoquinas/genética , Adipoquinas/metabolismo , Factores de Edad , Animales , Bebidas/efectos adversos , Biomarcadores/metabolismo , Tamaño de la Célula , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Progresión de la Enfermedad , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/prevención & control , Hiperglucemia/etiología , Hiperglucemia/prevención & control , Hiperinsulinismo/etiología , Hiperinsulinismo/prevención & control , Masculino , Obesidad/metabolismo , Obesidad/patología , Obesidad/fisiopatología , Distribución Aleatoria , Ratas WistarRESUMEN
Fat accumulation in the liver is a natural process in goose, which prepares goose for long-distance migration. In contrast to mammalian fatty liver that usually progresses into an irreversible status, steatohepatitis, goose fatty liver can return to normal without obvious pathological damage, suggesting a protective system exists in goose liver. This study was to identify the components of this system. We first focused on goose adiponectin receptor 1 and 2 (Adipor1/2) as they have ceramidase activity, and can cleave ceramide, a group of proinflammatory signaling lipid species. Quantitative analysis indicated that tumor necrosis factor alpha (Tnfα), a key proinflammatory cytokine, was down-regulated in goose fatty liver by overfeeding. This inhibition of Tnfα was accompanied with reduced adiponectin and increased Adipor1/2 in the adipose tissues and in the livers of the overfed geese, respectively. To investigate the regulation of goose Adipor2 in the context of fatty liver, we treated goose primary hepatocytes with fatty liver associated factors. Data indicated that Adipor2 was upregulated by glucose and oleate but not palmitate. Its expression was even suppressed by high level of insulin. The regulation of Adipor1 by these factors was quite similar to that of Adipor2 except that glucose did not induce Adipor1. Together, these findings suggest the upregulation of Adipor1/2 may, at least partially, contribute to the inhibition of inflammation in goose fatty liver, and the expression of Adipor1/2 can be regulated by fatty liver-associated factors.
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Proteínas Aviares/metabolismo , Hígado Graso/veterinaria , Gansos , Regulación de la Expresión Génica , Hígado/metabolismo , Enfermedades de las Aves de Corral/metabolismo , Receptores de Adiponectina/metabolismo , Grasa Abdominal/inmunología , Grasa Abdominal/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Animales , Animales Endogámicos , Proteínas Aviares/agonistas , Proteínas Aviares/genética , Células Cultivadas , China , Progresión de la Enfermedad , Embrión no Mamífero/citología , Nutrición Enteral/efectos adversos , Nutrición Enteral/veterinaria , Hígado Graso/etiología , Hígado Graso/metabolismo , Hígado Graso/fisiopatología , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/efectos adversos , Glucosa/metabolismo , Insulina/farmacología , Lipotrópicos/farmacología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/patología , Masculino , Ácido Oléico/efectos adversos , Ácido Oléico/metabolismo , Enfermedades de las Aves de Corral/etiología , Enfermedades de las Aves de Corral/inmunología , Enfermedades de las Aves de Corral/fisiopatología , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The increasing incidence of the metabolic syndrome (MetS), a combination of risk factors before the onset of CVD and type 2 diabetes, encourages studies on the role of functional food components such as long-chain n-3 PUFA as preventive agents. In the present study, we explore the effect of EPA and DHA supplementation in different proportions on spontaneously hypertensive obese (SHROB) rats, a model for the MetS in a prediabetic state with mild oxidative stress. SHROB rats were randomised into four groups (n 7), each supplemented with EPA/DHA at ratios of 1:1, 2:1 and 1:2, or soyabean oil as the control for 13 weeks. The results showed that in all the proportions tested, EPA/DHA supplementation significantly lowered total and LDL-cholesterol concentrations, compared with those of the control group. EPA/DHA supplementation at the ratios of 1:1 and 2:1 significantly decreased inflammation (C-reactive protein levels) and lowered oxidative stress (decreased excretion of urinary isoprostanes), mainly at the ratio of 1:2. The activity of antioxidant enzymes increased in erythrocytes, abdominal fat and kidneys, with magnitudes depending on the EPA:DHA ratio. PUFA mixtures from fish affected different MetS markers of CVD risk factors in SHROB rats, depending on the ratios of EPA/DHA supplementation. The activation of endogenous defence systems may be related to the reduction of inflammation and oxidative stress.
Asunto(s)
Suplementos Dietéticos , Ácidos Docosahexaenoicos/uso terapéutico , Ácido Eicosapentaenoico/uso terapéutico , Hipertensión/prevención & control , Síndrome Metabólico/dietoterapia , Obesidad/complicaciones , Estado Prediabético/prevención & control , Grasa Abdominal/enzimología , Grasa Abdominal/inmunología , Grasa Abdominal/metabolismo , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Biomarcadores/orina , Proteína C-Reactiva/análisis , Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Eritrocitos/enzimología , Eritrocitos/inmunología , Eritrocitos/metabolismo , Femenino , Aceites de Pescado/administración & dosificación , Aceites de Pescado/uso terapéutico , Hipercolesterolemia/etiología , Hipercolesterolemia/prevención & control , Hipertensión/etiología , Riñón/enzimología , Riñón/inmunología , Riñón/metabolismo , Síndrome Metabólico/complicaciones , Síndrome Metabólico/inmunología , Síndrome Metabólico/fisiopatología , Estrés Oxidativo , Oxidorreductasas/sangre , Oxidorreductasas/metabolismo , Estado Prediabético/etiología , Distribución Aleatoria , Ratas MutantesRESUMEN
In inflammatory bowel disease (IBD), obesity is associated with worsening of the course of disease. Here, we examined the role of obesity in the development of colitis and studied mesenteric fat-epithelial cell interactions in patients with IBD. We combined the diet-induce obesity with the trinitrobenzene sulfonic acid (TNBS) colitis mouse model to create groups with obesity, colitis, and their combination. Changes in the mesenteric fat and intestine were assessed by histology, myeloperoxidase assay, and cytokine mRNA expression by real-time PCR. Medium from human mesenteric fat and cultured preadipocytes was obtained from obese patients and those with IBD. Histological analysis showed inflammatory cell infiltrate and increased histological damage in the intestine and mesenteric fat of obese mice with colitis compared with all other groups. Obesity also increased the expression of proinflammatory cytokines including IL-1ß, TNF-α, monocyte chemoattractant protein 1, and keratinocyte-derived chemokine, while it decreased the TNBS-induced increases in IL-2 and IFN-γ in mesenteric adipose and intestinal tissues. Human mesenteric fat isolated from obese patients and those with and IBD demonstrated differential release of adipokines and growth factors compared with controls. Fat-conditioned media reduced adiponectin receptor 1 (AdipoR1) expression in human NCM460 colonic epithelial cells. AdipoR1 intracolonic silencing in mice exacerbated TNBS-induced colitis. In conclusion, obesity worsens the outcome of experimental colitis, and obesity- and IBD-associated changes in adipose tissue promote differential mediator release in mesenteric fat that modulates colonocyte responses and may affect the course of colitis. Our results also suggest an important role for AdipoR1 for the fat-intestinal axis in the regulation of inflammation during colitis.
Asunto(s)
Grasa Abdominal/metabolismo , Adipocitos Blancos/metabolismo , Colitis/etiología , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Obesidad/complicaciones , Receptores de Adiponectina/metabolismo , Grasa Abdominal/inmunología , Adipocitos Blancos/inmunología , Adipoquinas/genética , Adipoquinas/metabolismo , Animales , Estudios de Casos y Controles , Células Cultivadas , Colitis/inducido químicamente , Colitis/genética , Colitis/inmunología , Colitis/metabolismo , Colitis/patología , Colon/inmunología , Colon/metabolismo , Colon/patología , Medios de Cultivo Condicionados/metabolismo , Citocinas/genética , Citocinas/inmunología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Mediadores de Inflamación/inmunología , Masculino , Ratones Endogámicos C57BL , Obesidad/genética , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/patología , Interferencia de ARN , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal , Factores de Tiempo , Ácido TrinitrobencenosulfónicoRESUMEN
OBJECTIVE: To evaluate the association between waist-to-height ratio (WHtR) and specific biomarkers of inflammation, CVD risk and endothelial dysfunction in prepubertal obese children. DESIGN: Prospective, multicentre case-control study matched by age and sex. SETTING: Children were recruited between May 2007 and May 2010 from primary-care centres and schools in three cities in Spain (Cordoba, Santiago de Compostela and Zaragoza). SUBJECTS: Four hundred and forty-six (223 normal weight and 223 obese) Caucasian prepubertal children aged 6-12 years. RESULTS: WHtR was higher in the obese than in the normal-weight children. Blood pressure, waist circumference, weight, height, insulin, plasma lipids, leptin, resistin, abnormal neutrophil and monocyte counts, C-reactive protein, IL-6, IL-8, TNF-α, myeloperoxidase, soluble intercellular adhesion molecule-1, selectin and plasminogen activator inhibitor-1 levels were higher in the obese than in the normal-weight group. Adiponectin and HDL-cholesterol were lower and glucose and metalloproteinase-9 showed no differences. Resistin, TNF-α and active plasminogen activator inhibitor-1 were associated with WHtR, a sensitive indicator of central obesity. CONCLUSIONS: Our results lead to the hypothesis that changes in biomarker levels of insulin resistance, inflammation and CVD risk before puberty might induce metabolic consequences of obesity in obese children before reaching adulthood.
Asunto(s)
Grasa Abdominal/inmunología , Adipoquinas/sangre , Adiposidad , Enfermedades Cardiovasculares/etiología , Mediadores de Inflamación/sangre , Obesidad Abdominal/fisiopatología , Obesidad Infantil/fisiopatología , Grasa Abdominal/metabolismo , Adipoquinas/metabolismo , Biomarcadores/sangre , Índice de Masa Corporal , Enfermedades Cardiovasculares/epidemiología , Estudios de Casos y Controles , Niño , Fenómenos Fisiológicos Nutricionales Infantiles , Femenino , Humanos , Resistencia a la Insulina , Masculino , Obesidad Abdominal/sangre , Obesidad Abdominal/inmunología , Obesidad Abdominal/metabolismo , Obesidad Infantil/sangre , Obesidad Infantil/inmunología , Obesidad Infantil/metabolismo , Estudios Prospectivos , Factores de Riesgo , España/epidemiología , Relación Cintura-EstaturaRESUMEN
PURPOSE: To evaluate the long-term consequences of TNFα inhibitors on body composition and fat distribution, as well as changes in serum adipokines in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS). METHODS: Eight patients with RA and twelve with AS requiring a TNFα inhibitor were prospectively followed for 2 years. Body composition was evaluated by dual X-ray absorptiometry and included measurements of total fat mass, lean mass, fat in the gynoid and android regions, and visceral fat. Serum leptin, total and high molecular weight (HMW) adiponectin, resistin, and ghrelin were also assessed. RESULTS: There was a significant gain in body mass index (p = 0.05) and a tendency for weight (p = 0.07), android fat (p = 0.07), and visceral fat (p = 0.059) increase in patients with RA, while in AS, total fat mass significantly increased (p = 0.02) with a parallel weight gain (p = 0.07). When examining the whole population of patients, we observed after 2 years a significant increase in body weight (+1.9%; p = 0.003), body mass index (+2.5%; p = 0.004), total fat mass (+11.1%; p = 0.007), and fat in the android region (+18.3%; p = 0.02). There was a substantial, albeit nonsignificant gain in visceral fat (+24.3%; p = 0.088). Lean mass and gynoid fat were not modified. No major changes were observed for serum leptin, total adiponectin, and ghrelin, while HMW adiponectin and the HMW/total adiponectin ratio tended to decrease (-15.2%, p = 0.057 and -9.3%, p = 0.067, respectively). Resistin decreased significantly (-22.4%, p = 0.01). CONCLUSIONS: Long-term TNFα inhibition in RA and AS is associated with a significant gain in fat mass, with a shift to the android (visceral) region. This fat redistribution raises questions about its influence on the cardiovascular profile of patients receiving these treatments.
Asunto(s)
Grasa Abdominal/efectos de los fármacos , Adiposidad/efectos de los fármacos , Antiinflamatorios no Esteroideos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Espondilitis Anquilosante/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Grasa Abdominal/inmunología , Grasa Abdominal/metabolismo , Grasa Abdominal/patología , Adiponectina/antagonistas & inhibidores , Adiponectina/sangre , Adiponectina/metabolismo , Adulto , Antiinflamatorios no Esteroideos/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Índice de Masa Corporal , Monitoreo de Drogas , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina G/efectos adversos , Inmunoglobulina G/uso terapéutico , Resistencia a la Insulina , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resistina/antagonistas & inhibidores , Resistina/sangre , Resistina/metabolismo , Espondilitis Anquilosante/inmunología , Espondilitis Anquilosante/metabolismo , Espondilitis Anquilosante/patología , Aumento de Peso/efectos de los fármacosRESUMEN
OBJECTIVE: To examine if, as in obesity, pregnancies complicated by gestational diabetes mellitus (GDM) exhibit increased macrophage infiltration and activated MAP-kinases in omental adipose tissue. METHODS: Paired omental (OM) and abdominal subcutaneous (SC) fat samples were collected from 11 GDM and 20 normal pregnancies during cesarean delivery. Tissues were stained to detect macrophages, and analyzed to assess MAP-kinases. RESULTS: OM had higher macrophage counts than SC in GDM (6.10 ± 2.20 versus 2.53 ± 1.45, p = 0.04), but not in normal pregnancies (p = 0.346). GDM pregnancies had more macrophages than normal pregnancies in OM (6.10 ± 2.20 versus 1.29 ± 0.55, p = 0.01), while only a trend was observed in SC fat (p = 0.08). Significant correlation (R = 0.619, p = 0.005) was observed between OM-macrophage infiltration and insulin resistance. Using multivariate analysis, only obesity independently associated with GDM. Expression of total p38MAP-kinase was higher in OM versus SC in both normal and GDM pregnancies, without significant differences between these groups. However, expression of activated p-p38MAP-kinase, and its upstream kinase MKK4, was comparable between fat depots. CONCLUSION: GDM pregnancies demonstrate increased macrophage infiltration to OM fat, correlating with higher insulin resistance. As in non-pregnant-patients obesity and OM macrophage infiltration may be on the same causal pathway, leading to GDM. Yet, this occurs without activation of p38MAP-kinase signaling.
Asunto(s)
Grasa Abdominal , Movimiento Celular , Diabetes Gestacional , Macrófagos/fisiología , Estrés Fisiológico , Grasa Subcutánea , Grasa Abdominal/inmunología , Grasa Abdominal/metabolismo , Adulto , Estudios de Casos y Controles , Movimiento Celular/inmunología , Diabetes Gestacional/inmunología , Diabetes Gestacional/metabolismo , Femenino , Humanos , MAP Quinasa Quinasa 4/metabolismo , Epiplón , Embarazo , Transducción de Señal , Grasa Subcutánea/inmunología , Grasa Subcutánea/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Fish oils (FOs) have anti-inflammatory effects and lower serum triglycerides. This study examined adipose and muscle inflammatory markers after treatment of humans with FOs and measured the effects of ω-3 fatty acids on adipocytes and macrophages in vitro. Insulin-resistant, nondiabetic subjects were treated with Omega-3-Acid Ethyl Esters (4 g/day) or placebo for 12 weeks. Plasma macrophage chemoattractant protein 1 (MCP-1) levels were reduced by FO, but the levels of other cytokines were unchanged. The adipose (but not muscle) of FO-treated subjects demonstrated a decrease in macrophages, a decrease in MCP-1, and an increase in capillaries, and subjects with the most macrophages demonstrated the greatest response to treatment. Adipose and muscle ω-3 fatty acid content increased after treatment; however, there was no change in insulin sensitivity or adiponectin. In vitro, M1-polarized macrophages expressed high levels of MCP-1. The addition of ω-3 fatty acids reduced MCP-1 expression with no effect on TNF-α. In addition, ω-3 fatty acids suppressed the upregulation of adipocyte MCP-1 that occurred when adipocytes were cocultured with macrophages. Thus, FO reduced adipose macrophages, increased capillaries, and reduced MCP-1 expression in insulin-resistant humans and in macrophages and adipocytes in vitro; however, there was no measureable effect on insulin sensitivity.
Asunto(s)
Grasa Abdominal/inmunología , Suplementos Dietéticos , Ácidos Grasos Omega-3/uso terapéutico , Resistencia a la Insulina , Macrófagos/inmunología , Síndrome Metabólico/dietoterapia , Obesidad/complicaciones , Grasa Abdominal/irrigación sanguínea , Grasa Abdominal/metabolismo , Grasa Abdominal/patología , Inductores de la Angiogénesis/metabolismo , Inductores de la Angiogénesis/uso terapéutico , Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Índice de Masa Corporal , Capilares/inmunología , Capilares/metabolismo , Capilares/patología , Células Cultivadas , Quimiocina CCL2/sangre , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Técnicas de Cocultivo , Ácidos Docosahexaenoicos , Regulación hacia Abajo , Combinación de Medicamentos , Ácido Eicosapentaenoico , Ácidos Grasos Omega-3/metabolismo , Femenino , Aceites de Pescado/uso terapéutico , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/inmunología , Síndrome Metabólico/metabolismo , Persona de Mediana Edad , Músculos/inmunología , Músculos/metabolismo , Músculos/patología , ARN Mensajero/metabolismoRESUMEN
OBJECTIVES: (1) To investigate whether modulation of the cannabinoid type 1 receptor (CB1R) directly regulates the production of adiponectin (ApN) and other adipokines in omental adipose tissue (OAT) of obese subjects, (2) to establish in which cellular fraction of OAT the effects of CB1R blockade take place and (3) to unravel the underlying mechanisms. SUBJECTS AND METHODS: OAT was obtained from 30 obese subjects (body mass index: 40.6±1.3 kg m(-2)) undergoing abdominal surgery. Primary cultures of explants or of freshly isolated adipocytes or stromal-vascular cells (SVCs) were used. RESULTS: In OAT explants, the CB1R blocker Rimonabant upregulated ApN gene expression. mRNA abundance of omentin that exhibits insulin-sensitizing properties was upregulated as well. Conversely, mRNA levels of two pro-inflammatory cytokines, macrophage inflammatory protein (MIP)-1ß and interleukin (IL)-7 were downregulated. We next examined where these effects took place within OAT. CB1R expression was similar in both cellular fractions. In isolated mature adipocytes, blockade of CB1R reproduced the increase of ApN mRNA and the decrease of IL-7 mRNA, while inducing a rise of ApN secretion into the medium. In isolated SVC, gene expression of omentin, which is restricted to this fraction, was augmented, while that of MIP-1ß was diminished. Finally, we deciphered the mechanisms leading to ApN regulation by the endocannabinoid system (ES). We first established that ApN regulation was actually mediated by the CB1R: ApN gene expression was upregulated by Rimonabant and downregulated by the CB1R agonist arachidonyl-2-chloroethylamide (ACEA). Upregulation of ApN by Rimonabant was unaltered by inhibiting cAMP production. However, downregulation of ApN by ACEA was fully reversed by an inhibitor of p38 mitogen-activated protein kinase (p38MAPK) and ACEA increased p38MAPK phosphorylation. CONCLUSIONS: Blockade of CB1R attenuates the inflammatory state in both cellular fractions of OAT either by increasing ApN and omentin production or by decreasing mRNAs of MIP-1ß and IL-7. ApN regulation by the ES partly involves p38MAPK.