RESUMEN
BACKGROUND/OBJECTIVES: OxLDL-ß2GPI complex has been suggested to have a role in the development of atherosclerosis and other inflammatory diseases. The aim of this study was to investigate the possible association of circulating oxLDL-ß2GPI with obesity-induced inflammatory state of adipose tissue and related comorbidities as metabolic syndrome development. SUBJECTS/METHODS: Two cohorts of subjects were examined in the study. Cohort I: 36 women with wide range of body mass index (17-48 kg m-2) and metabolic status (with or without metabolic syndrome (MS); cohort II: 20 obese women undergoing a dietary intervention (DI) consisting of 1-month very-low-calorie diet, and 5 months of weight-stabilization period. Serum levels of oxLDL-ß2GPI were measured by enzyme-linked immunosorbent assay. Insulin sensitivity was evaluated by hyperinsulinemic-euglycemic clamp and homeostasis model assessment of insulin resistance. mRNA expression of macrophage markers was determined in both subcutaneous (SAT) and visceral (VAT) adipose tissue in cohort I and in SAT in cohort II. RESULTS: Serum oxLDL-ß2GPI levels were increased in obese subjects with MS compared to lean or obese without MS (obese with MS: 26.6±5.0 vs lean: 15.17±1.97, P<0.001; vs obese without MS: 16.36±2.89, P<0.05). Serum oxLDL-ß2GPI correlated with MS indices (glucose, high-density lipoprotein, triglyceride and ureic acid) and with mRNA expression of macrophage markers in VAT. Weight-reducing DI decreased serum oxLDL-ß2GPI levels together with lipid parameters and the mRNA expression of inflammatory markers in SAT. CONCLUSIONS: OxLDL-ß2GPI seems to be an important marker of visceral adipose tissue inflammation and possibly a factor contributing to insulin resistance and metabolic syndrome development in obese patients.
Asunto(s)
Tejido Adiposo/fisiopatología , Inflamación/sangre , Lipoproteínas LDL/sangre , Síndrome Metabólico/sangre , Obesidad , beta 2 Glicoproteína I/sangre , Tejido Adiposo/metabolismo , Adulto , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Inflamación/fisiopatología , Lipoproteínas LDL/química , Lipoproteínas LDL/metabolismo , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Complejos Multiproteicos , Obesidad/sangre , Obesidad/metabolismo , Obesidad/fisiopatología , beta 2 Glicoproteína I/química , beta 2 Glicoproteína I/metabolismoRESUMEN
Chronic lymphoedema is a disease caused by a congenital or acquired damage to the lymphatic system and characterized by complex chains of pathophysiologic events such as lymphatic fluid stasis, chronic inflammation, lymphatic vessels impairment, adipose tissue deposition and fibrosis. These events seem to maintain and reinforce themselves through a positive feedback loop: regardless of the initial cause of lymphatic stasis, the dysfunctional adipose tissue and its secretion products can worsen lymphatic vessels' function, aggravating lymph leakage and stagnation, which can promote further adipose tissue deposition and fibrosis, similar to what may happen in obesity. In addition to the current knowledge about the tight and ancestral interrelation between immunity system and metabolism, there is evidence for similarities between obesity-related and lymphatic damage-induced lymphoedema. Together, these observations indicate strong reciprocal relationship between lymphatics and adipose tissue and suggest a possible key role of the adipocyte in the pathophysiology of chronic lymphoedema's vicious circle.
Asunto(s)
Adipocitos/fisiología , Linfedema/etiología , Enfermedad Crónica , Fibrosis , Humanos , Vasos Linfáticos/fisiopatología , Linfedema/patología , Linfedema/fisiopatologíaRESUMEN
BACKGROUND/OBJECTIVES: Branched chain amino acids (BCAA) are among nutrients strongly linked with insulin sensitivity (IS) measures. We investigated the effects of a chronic increase of BCAA intake on IS in two groups of healthy subjects differing in their basal consumption of BCAA, that is, vegans and omnivores. SUBJECTS/METHODS: Eight vegans and eight matched omnivores (five men and three women in each group) received 15 g (women) or 20 g (men) of BCAA daily for 3 months. Anthropometry, blood analyses, glucose clamp, arginine test, subcutaneous abdominal adipose tissue (AT) and skeletal muscle (SM) biopsies (mRNA levels of selected metabolic markers, respiratory chain (RC) activity) were performed at baseline, after the intervention and after a 6 month wash-out period. RESULTS: Compared with omnivores, vegans had higher IS at baseline (GIR, glucose infusion rate: 9.6±2.4 vs 7.1±2.4 mg/kg/min, 95% CI for difference: 0.55 to 5.82) that declined after the intervention and returned to baseline values after the wash-out period (changes in GIR with 95% CI, 3-0 months: -1.64 [-2.5; -0.75] and 9-3 months: 1.65 [0.75; 2.54] mg/kg/min). No such change was observed in omnivores. In omnivores the intervention led to an increased expression of lipogenic genes (DGAT2, FASN, PPARγ, SCD1) in AT. SM RC activity increased in both groups. CONCLUSIONS: Negative impact of increased BCAA intake on IS was only detected in vegans, that is, subjects with low basal amino acids/BCAA intake, which appear to be unable to induce sufficient compensatory changes within AT and SM on a BCAA challenge.
Asunto(s)
Aminoácidos de Cadena Ramificada/administración & dosificación , Glucemia/metabolismo , Exposición Dietética/efectos adversos , Veganos , Adulto , Aminoácidos de Cadena Ramificada/sangre , Antropometría , Dieta , Dieta Vegana , Proteínas en la Dieta/administración & dosificación , Relación Dosis-Respuesta a Droga , Ejercicio Físico , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Resistencia a la Insulina , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Estudios Prospectivos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Accumulation of adipose tissue in lower body lowers risk of cardiovascular and metabolic disorders. The molecular basis of this protective effect of gluteofemoral depot is not clear. The aim of this study was to compare the profile of expression of inflammation-related genes in subcutaneous gluteal (sGAT) and abdominal (sAAT) adipose tissue at baseline and in response to multiphase weight-reducing dietary intervention (DI). 14 premenopausal healthy obese women underwent a 6 months' DI consisting of 1 month very-low-calorie-diet (VLCD), subsequent 2 months' low-calorie-diet and 3 months' weight maintenance diet (WM). Paired samples of sGAT and sAAT were obtained before and at the end of VLCD and WM periods. mRNA expression of 17 genes (macrophage markers, cytokines) was measured using RT-qPCR on chip-platform. At baseline, there were no differences in gene expression of macrophage markers and cytokines between sGAT and sAAT. The dynamic changes induced by DI were similar in both depots for all genes except for three cytokines (IL6, IL10, CCL2) that differed in their response during weight maintenance phase. The results show that, in obese women, there are no major differences between sGAT and sAAT in expression of inflammation-related genes at baseline conditions and in response to the weight-reducing DI.
Asunto(s)
Dieta Reductora , Regulación de la Expresión Génica , Mediadores de Inflamación/metabolismo , Obesidad/metabolismo , Grasa Subcutánea Abdominal/metabolismo , Tejido Adiposo/metabolismo , Adulto , Peso Corporal/fisiología , Nalgas/fisiología , Dieta Reductora/métodos , Femenino , Humanos , Persona de Mediana Edad , Obesidad/dietoterapiaRESUMEN
Hypocaloric diet is a key component of the weight-reducing treatment of obesity and obesity-related disorders. Hypocaloric diets and the associated weight reduction promote improvement of metabolic profile of obese individuals. Among the mechanisms that underlie this beneficial metabolic outcome, the diet-induced modifications of morphological and functional characteristics of human adipose tissue (AT) are believed to have an important role. Prospective studies of hypocaloric weight-reducing dietary intervention demonstrate effects on adipocyte metabolism, namely lipolysis and lipogenesis, and associated changes of the adipocyte size. The endocrine function of AT, which involves cytokine and adipokine production by adipocytes, as well as by cells of stromavascular fraction, is also regulated by dietary intervention. Related inflammatory status of AT is modulated also as a consequence of the changes in recruitment of immune cells, mainly macrophages, in AT. Here, we give an overview of metabolic and endocrine modifications in human AT induced by a variety of hypocaloric diets.
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Adipocitos/patología , Tejido Adiposo/metabolismo , Restricción Calórica , Inflamación/metabolismo , Lipogénesis , Lipólisis , Obesidad/metabolismo , Adaptación Fisiológica/inmunología , Adipocitos/metabolismo , Tejido Adiposo/inmunología , Índice de Masa Corporal , Dieta Reductora , Conducta Alimentaria , Femenino , Humanos , Inflamación/inmunología , Macrófagos/inmunología , Masculino , Obesidad/inmunología , Obesidad/fisiopatología , Estudios Prospectivos , Resultado del Tratamiento , Pérdida de Peso/inmunologíaRESUMEN
OBJECTIVE: Hypoadiponectinemia observed in obesity is associated with insulin resistance, diabetes and atherosclerosis. The aim of the present study was to investigate secretion of adiponectin and its multimeric isoforms by explants derived from subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese and non-obese subjects. DESIGN: Paired samples of SAT and VAT and blood samples were obtained from 23 subjects (10 non-obese and 13 obese) undergoing elective abdominal surgery. Total adiponectin quantities and adiponectin isoforms were measured in conditioned media of explants derived from SAT and VAT using enzyme-linked immunosorbent assay and non-denaturing western blot, respectively. RESULTS: Total adiponectin plasma levels were lower in obese than in non-obese subjects (P<0.05). Secretion of total adiponectin in adipose tissue (AT) explants was lower in obese than in non-obese subjects in SAT (P<0.05) but not in VAT. In both, SAT and VAT, the most abundant isoform released into conditioned media was the high-molecular weight (HMW) form. Its relative proportion in relation to total adiponectin was higher in conditioned media of explants from both fat depots when compared with plasma (P<0.001). The proportion of secreted HMW vs total adiponectin was higher in VAT than in SAT explants in the group of non-obese individuals (49.3±3.1% in VAT vs 40.6±2.8% in SAT; P<0.01), whereas no difference between the two depots was found in obese subjects (46.2±3.0 % in VAT vs 46.0±2.4 % in SAT). CONCLUSION: Obesity is associated with the decrease of total adiponectin secretion in SAT. The profile of adiponectin isoforms secreted by SAT and VAT explants differs from that in plasma. Secretion of total adiponectin and HMW isoform of adiponectin are different in obese and non-obese subjects in relation to AT depot.
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Adiponectina/sangre , Aterosclerosis/sangre , Diabetes Mellitus Tipo 2/sangre , Grasa Intraabdominal/metabolismo , Obesidad/sangre , Grasa Subcutánea/metabolismo , Adulto , Aterosclerosis/fisiopatología , Aterosclerosis/prevención & control , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/prevención & control , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/fisiopatología , Isoformas de Proteínas/sangreRESUMEN
OBJECTIVE: Accumulation of adipose tissue macrophages (ATMs) is observed in obesity and may participate in the development of insulin resistance and obesity-related complications. The aim of our study was to investigate the effect of long-term dietary intervention on ATM content in human adipose tissue. DESIGN: We performed a multi-phase longitudinal study. SUBJECTS AND MEASUREMENTS: A total of 27 obese pre-menopausal women (age 39 ± 2 years, body mass index 33.7 ± 0.5 kg m(-2)) underwent a 6-month dietary intervention consisting of two periods: 4 weeks of very low-calorie diet (VLCD) followed by weight stabilization composed of 2 months of low-calorie diet and 3 to 4 months of weight maintenance diet. At baseline and at the end of each dietary period, samples of subcutaneous adipose tissue (SAT) were obtained by needle biopsy and blood samples were drawn. ATMs were determined by flow cytometry using combinations of cell surface markers. Selected cytokine and chemokine plasma levels were measured using enzyme-linked immunosorbent assay. In addition, in a subgroup of 16 subjects, gene expression profiling of macrophage markers in SAT was performed using real-time PCR. RESULTS: Dietary intervention led to a significant decrease in body weight, plasma insulin and C-reactive protein levels. After VLCD, ATM content defined by CD45+/14+/206+ did not change, whereas it decreased at the end of the intervention. This decrease was associated with a downregulation of macrophage marker mRNA levels (CD14, CD163, CD68 and LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1)) and plasma levels of monocyte-chemoattractant protein-1 (MCP-1) and CXCL5 (chemokine (C-X-C motif) ligand 5). During the whole dietary intervention, the proportion of two ATM subpopulations distinguished by the CD16 marker was not changed. CONCLUSION: A 6-month weight-reducing dietary intervention, but not VLCD, promotes a decrease in the number of the whole ATM population with no change in the relative distribution of ATM subsets.
Asunto(s)
Tejido Adiposo Blanco/patología , Dieta Reductora , Macrófagos/patología , Obesidad/patología , Pérdida de Peso , Adulto , Índice de Masa Corporal , Peso Corporal , Proteína C-Reactiva/genética , Quimiocina CXCL5/genética , Regulación hacia Abajo , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Estudios Longitudinales , Obesidad/dietoterapia , Obesidad/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas de Transporte Vesicular/genética , Pérdida de Peso/genéticaRESUMEN
Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2'-deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon gamma (IFNgamma), IFNbeta and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNbeta-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.