RESUMEN
Obese adipose tissue (AT) inflammation is partly driven by accumulation of CD4+ T helper (Th)1 cells and reduced Th2 and T regulatory subsets, which promotes macrophage chemotaxis and ensuing AT metabolic dysfunction. This study investigated CD4+ T cell/adipocyte cytokine-mediated paracrine interactions (cross talk) as a target for dietary intervention to mitigate obese AT inflammation. Using an in vitro co-culture model designed to recapitulate CD4+ T cell accumulation in obese AT (5% of stromal vascular cellular fraction), 3T3-L1 adipocytes were co-cultured with purified splenic CD4+ T cells from C57Bl/6 mice consuming one of two isocaloric diets containing either 10% w/w safflower oil (control, CON) or 7% w/w safflower oil+3% w/w fish oil (FO) for 4 weeks (n=8-11/diet). The FO diet provided 1.9% kcal from the long-chain (LC) n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid and docosahexaenoic acid, a dose that can be achieved by supplementation. Co-cultures were stimulated for 48 h with lipopolysaccharide (LPS) to mimic in vivo obese endotoxin levels or with conditioned media collected from LPS-stimulated visceral AT isolated from CON-fed mice. In both stimulation conditions, FO reduced mRNA expression and/or secreted protein levels of Th1 markers (T-bet, IFN-γ) and increased Th2 markers (GATA3, IL-4), concomitant with reduced inflammatory cytokines (IL-1ß, IL-6, IL-12p70, TNF-α), macrophage chemokines (MCP-1, MCP-3, MIP-1α, MIP-2) and levels of activated central regulators of inflammatory signaling (NF-κB, STAT-1, STAT-3) (P<.05). Therefore, CD4+ T cell/adipocyte cross talk represents a potential target for LC n-3 PUFAs to mitigate obese AT inflammation.
Asunto(s)
Adipocitos/inmunología , Linfocitos T CD4-Positivos/citología , Ácidos Grasos Omega-3/metabolismo , Inflamación/tratamiento farmacológico , Obesidad/inmunología , Células 3T3-L1 , Tejido Adiposo/inmunología , Animales , Quimiocinas/metabolismo , Técnicas de Cocultivo , Dieta , Modelos Animales de Enfermedad , Femenino , Aceites de Pescado/metabolismo , Inflamación/sangre , Inflamación/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Subunidad p50 de NF-kappa B/metabolismo , Obesidad/sangre , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
Vitamin D status has been implicated in obesity and adipose tissue inflammation. In the present study, we explored the effects of dietary vitamin D supplementation on adipose tissue inflammation and immune cell population, and the effects of in vitro 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) treatment on pro-inflammatory cytokine production by stromal vascular cells (SVCs) and adipocytes in lean and high-fat diet-induced obese mice. The results show that epididymal fat Mcp-1 and Rantes mRNA levels, which were higher in obese mice compared with lean mice, were significantly down-regulated by vitamin D supplementation. While obese mice had higher numbers of macrophages and natural killer (NK) cells within adipose tissue, these remained unaltered by vitamin D supplementation. In accordance with these in vivo findings, the in vitro 1,25(OH)2D3 treatment decreased IL-6, MCP-1, and IL-1ß production by SVCs from obese mice, but not by adipocytes. In addition, 1,25(OH)2D3 treatment significantly decreased Tlr2 expression and increased mRNA levels of Iκba and Dusp1 in SVCs. These findings suggest that vitamin D supplementation attenuates inflammatory response in adipose tissue, especially in SVCs, possibly through inhibiting NF-κB and MAPK signaling pathways in SVCs but not by the inhibition of macrophage infiltration.
Asunto(s)
Adipocitos/efectos de los fármacos , Calcitriol/farmacología , Obesidad/inmunología , Células del Estroma/efectos de los fármacos , Vitaminas/farmacología , Adipocitos/inmunología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/inmunología , Animales , Citocinas/efectos de los fármacos , Citocinas/inmunología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Inflamación , Ratones , Ratones Obesos , Obesidad/terapia , Células del Estroma/inmunologíaRESUMEN
BACKGROUND AND OBJECTIVE: Our patient cohort revealed that obesity is strongly associated with steroid-5α reductase type 2 (SRD5A2) promoter methylation and reduced protein expression. The underlying mechanism of prostatic growth in this population is poorly understood. Here we addressed the question of how obesity, inflammation, and steroid hormones affect the development of benign prostatic hyperplasia (BPH). MATERIAL AND METHODS: We used preadipocytes, macrophages, primary human prostatic stromal cells, prostate tissues from high-fat diet-induced obese mice, and 35 prostate specimens that were collected from patients who underwent transurethral resection of the prostate (TURP). RNA was isolated and quantified with RT-PCR. Genome DNA was extracted and SRD5A2 promoter methylation was determined. Sex hormones were determined by high-performance liquid chromatography-tandem mass spectrometry. Protein was extracted and determined by ELISA test. RESULTS: In prostatic tissues with obesity, the levels of inflammatory mediators were elevated. SRD5A2 promoter methylation was promoted, but SRD5A2 expression was inhibited. Inflammatory mediators and saturated fatty acid synergistically regulated aromatase activity. Obesity promoted an androgenic to estrogenic switch in the prostate. CONCLUSIONS: Our findings suggest that obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland, which may serve as an effective strategy for alternative therapies for management of lower urinary tract symptoms associated with BPH in select individuals.
Asunto(s)
Andrógenos/metabolismo , Estrógenos/metabolismo , Obesidad/inmunología , Próstata/patología , Hiperplasia Prostática/inmunología , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Células 3T3-L1 , Adipocitos/inmunología , Adipocitos/metabolismo , Anciano , Anciano de 80 o más Años , Andrógenos/análisis , Animales , Aromatasa/metabolismo , Metilación de ADN , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Estrógenos/análisis , Ácidos Grasos/metabolismo , Humanos , Mediadores de Inflamación/análisis , Mediadores de Inflamación/metabolismo , Metabolismo de los Lípidos/inmunología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/metabolismo , Cultivo Primario de Células , Regiones Promotoras Genéticas/genética , Próstata/citología , Próstata/inmunología , Próstata/cirugía , Hiperplasia Prostática/patología , Hiperplasia Prostática/cirugía , Células del Estroma , Células THP-1 , Resección Transuretral de la PróstataRESUMEN
Obesity is associated with an increased incidence of high-grade prostate cancer (PC) and worse prognosis for PC patients. Recently, we showed in men that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures, was associated with high-grade PC. Possibly, interventions that suppress periprostatic WAT inflammation will improve outcomes for men with PC. Here, we tested the hypothesis that supplemental 17ß-estradiol (E2) could decrease periprostatic WAT inflammation in obese male mice. Mice were fed a high-fat diet to induce periprostatic WAT inflammation before being treated with supplemental E2. E2 supplementation suppressed caloric intake, induced weight loss, decreased periprostatic WAT inflammation and downregulated the expression of genes linked to inflammation including Cd68, Mcp1 and Tnf. Similar to the effects of E2 supplementation, treatment with diethylstilbestrol, a synthetic estrogen, also suppressed caloric intake and reduced periprostatic WAT inflammation. To determine whether the observed effects of supplemental estrogen could be reproduced by caloric restriction (CR) alone, obese mice were put on a 30% CR diet. Like estrogen treatment, CR was effective in reducing body weight, periprostatic WAT inflammation and the expression of pro-inflammatory genes. Transcriptomic analyses of periprostatic fat showed that obesity was associated with enrichment in inflammatory response pathways, which were normalized by both supplemental E2 and CR. Taken together, these findings strengthen the rationale for future efforts to determine whether either CR or supplemental estrogen will decrease periprostatic WAT inflammation and thereby improve outcomes for men with PC.
Asunto(s)
Restricción Calórica , Estradiol/administración & dosificación , Estrógenos/administración & dosificación , Inflamación/terapia , Grasa Intraabdominal/efectos de los fármacos , Obesidad/complicaciones , Adipocitos/inmunología , Adipocitos/patología , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Humanos , Inflamación/inmunología , Inflamación/patología , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/patología , Masculino , Ratones , Obesidad/inmunología , Obesidad/terapia , Próstata/efectos de los fármacos , Próstata/inmunología , Próstata/patología , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacosRESUMEN
S-resistin, a non-secretable resistin isoform, acts as an intracrine factor that regulates adipocyte maduration, inflammatory and insulin response in 3T3-L1 cells. However, its intracellular function in vivo is still unknown. In this study, we analyze the central role of s-resistin, decreasing its hypothalamic expression using an intracerebroventricular injection of lentiviral RNAi. The data present herein support an improvement in the hypothalamic leptin and insulin signaling pathway upon s-resistin downregulation. Furthermore, hypothalamic levels of pro-inflammatory markers decrease, meanwhile those of the anti-inflammatory cytokine IL-10 increases. Interestingly, peripheral NEFA decreases alike circulating leptin and resistin levels. These data demonstrate that hypothalamic s-resistin controls fuel mobilization and adipokines secretion. Importantly, central s-resistin downregulation improves systemic insulin sensitivity, as demonstrated after an IPGTT. Interestingly, our data also indicate that s-resistin downregulation could improve hypothalamic inflammation in aged Wistar rats. Altogether, our findings suggest that hypothalamic s-resistin seems to be a key regulator of the brain-fat axis which links inflammation with metabolic homeostasis.
Asunto(s)
Adipocitos/metabolismo , Hipotálamo/metabolismo , Inflamación/prevención & control , Resistencia a la Insulina , Insulina/metabolismo , Resistina/antagonistas & inhibidores , Adipocitos/inmunología , Adipocitos/patología , Animales , Citocinas/metabolismo , Células HEK293 , Células HeLa , Homeostasis , Humanos , Hipotálamo/inmunología , Hipotálamo/patología , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , ARN Interferente Pequeño/genética , Ratas , Ratas Wistar , Resistina/genética , Resistina/metabolismoRESUMEN
This retrospective study attempts to establish if a correlation exists between osteoporosis and hematopoiesis before and after adjuvant chemotherapy in the context of non-metastatic breast cancer. Osteoporosis is interpreted both as a direct marker of osteoblastic decline and as an indirect marker of increased bone marrow adiposity within the hematopoietic microenvironment. Patients from the "Centre du Sein" at CHUV (Centre Hospitalier Universitaire Vaudois) undergoing adjuvant chemotherapy were included in this study. Evolution of blood counts was studied in correlation with the osteoporosis status. Toxicity of chemotherapy was coded according to published probability of febrile neutropenia. One hundred forty-three women were included: mean age 52.1 ± 12.5 years, mean BMI (body mass index) 24.4 ± 4.1. BMD (bone mineral density) scored osteoporotic in 32% and osteopenic in 45%. Prior to chemotherapy, BMD was positively correlated with neutrophil (p < 0.001) and thrombocyte (p = 0.01) count; TBS (trabecular bone score) was not correlated with blood count. After the first cycle of chemotherapy, an increase of one point in TBS correlated with a decrease of 57% on the time to reach leucocyte nadir (p = 0.004). There was a positive correlation between BMD and risk of infection (p < 0.001). Our data demonstrates an association between osteoporosis and lower blood counts in a younger cohort than previously published, extending it for the first time to neutrophil counts in females. Our results suggest that the healthier the bone, the earlier the lowest leucocyte count value, prompting further research on this area.
Asunto(s)
Antineoplásicos/administración & dosificación , Enfermedades Óseas Metabólicas/complicaciones , Neoplasias de la Mama/complicaciones , Quimioterapia Adyuvante , Neutropenia/inducido químicamente , Osteoporosis/complicaciones , Absorciometría de Fotón , Adipocitos/efectos de los fármacos , Adipocitos/inmunología , Adipocitos/patología , Adulto , Anciano , Antineoplásicos/efectos adversos , Plaquetas/efectos de los fármacos , Plaquetas/inmunología , Plaquetas/patología , Índice de Masa Corporal , Densidad Ósea/efectos de los fármacos , Densidad Ósea/inmunología , Enfermedades Óseas Metabólicas/diagnóstico por imagen , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Enfermedades Óseas Metabólicas/inmunología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Recuento de Células , Femenino , Hematopoyesis/efectos de los fármacos , Hematopoyesis/inmunología , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/efectos de los fármacos , Vértebras Lumbares/inmunología , Vértebras Lumbares/patología , Persona de Mediana Edad , Neutropenia/diagnóstico por imagen , Neutropenia/inmunología , Neutropenia/patología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/patología , Osteoblastos/efectos de los fármacos , Osteoblastos/inmunología , Osteoblastos/patología , Osteoporosis/diagnóstico por imagen , Osteoporosis/tratamiento farmacológico , Osteoporosis/inmunología , Estudios RetrospectivosRESUMEN
Adipose tissue hypoxia has been recognized as the initiation of insulin resistance syndromes. The aim of the present study was to investigate the effects of mangiferin on the insulin signaling pathway and explore whether mangiferin could ameliorate insulin resistance caused by hypoxia in adipose tissue. Differentiated 3T3-L1 adipocytes were incubated under normal and hypoxic conditions, respectively. Protein expressions were analyzed by Western blotting. Inflammatory cytokines and HIF-1-dependent genes were tested by ELISA and q-PCR, respectively. The glucose uptake was detected by fluorescence microscopy. HIF-1α was abundantly expressed during 8 h of hypoxic incubation. Inflammatory reaction was activated by up-regulated NF-κB phosphorylation and released cytokines like IL-6 and TNF-α. Glucose uptake was inhibited and insulin signaling pathway was damaged as well. Mangiferin substantially inhibited the expression of HIF-1α. Lactate acid and lipolysis, products released by glycometabolism and lipolysis, were also inhibited. The expression of inflammatory cytokines was significantly reduced and the damaged insulin signaling pathway was restored to proper functional level. The glucose uptake of hypoxic adipocytes was promoted and the dysfunction of adipocytes was relieved. These results showed that mangiferin could not only improve the damaged insulin signaling pathway in hypoxic adipocytes, but also ameliorate inflammatory reaction and insulin resistance caused by hypoxia.
Asunto(s)
Adipocitos/efectos de los fármacos , Adipoquinas/genética , Resistencia a la Insulina , Oxígeno/metabolismo , Xantonas/farmacología , Células 3T3-L1 , Adipocitos/inmunología , Adipoquinas/inmunología , Animales , Hipoxia de la Célula/efectos de los fármacos , Glucosa/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/inmunología , Insulina/metabolismo , Ratones , FN-kappa B/genética , FN-kappa B/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Crosstalk between adipocytes and macrophages has been suggested to play a crucial role in metabolic disorders such as obesity, insulin resistance, and type 2 diabetes. The objective of this study was to evaluate the effect of nobiletin on the interaction between adipocytes and macrophages. The results showed that nobiletin significantly and dose-dependently inhibited the secretion of inflammatory mediators, such as nitric oxide (NO), tumor necrosis factor (TNF-α), and monocyte chemoattractant protein (MCP)-1, in a coculture of adipocytes and macrophages. The expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), in differentiated 3T3-L1 cells cocultured in transwell system was blocked by nobiletin. Nobiletin also downregulated the expression of inducible NO synthase in cocultured differentiated RAW264.7 cells. Furthermore, heme oxygenase-1 (HO-1) was significantly induced by nobiletin treatment in both cell types, and small interfering (si) RNA-mediated knockdown of HO-1 significantly recovered the inhibitory effects of nobiletin on the NO production in cocultured cells. These results suggest that nobiletin exerts anti-inflammatory effects on the crosstalk between adipocytes and macrophages by inducing HO-1. Nobiletin may have potential for the prevention of obesity-related metabolic diseases.
Asunto(s)
Adipocitos/efectos de los fármacos , Flavonas/farmacología , Hemo-Oxigenasa 1/inmunología , Macrófagos/inmunología , Células 3T3-L1 , Adipocitos/inmunología , Animales , Proteína alfa Potenciadora de Unión a CCAAT/genética , Proteína alfa Potenciadora de Unión a CCAAT/inmunología , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Técnicas de Cocultivo , Hemo-Oxigenasa 1/genética , Macrófagos/efectos de los fármacos , Ratones , Células RAW 264.7RESUMEN
Metabolic inflammation is a very topical area of research, wherein aberrations in metabolic and inflammatory pathways probably contribute to atherosclerosis, insulin resistance (IR) and type 2 diabetes. Metabolic insults arising from obesity promote inflammation, which in turn impedes insulin signalling and reverse cholesterol transport (RCT). Key cells in the process are metabolically activated macrophages, which up-regulate both pro- and anti-inflammatory pathways in response to lipid spillover from adipocytes. Peroxisome proliferator-activated receptors and AMP-activated protein kinase (AMPK) are regulators of cellular homeostasis that influence both inflammatory and metabolic pathways. Dietary fats, such as saturated fatty acids (SFAs), can differentially modulate metabolic inflammation. Palmitic acid, in particular, is a well-characterized nutrient that promotes metabolic inflammation via the NLRP3 (the nod-like receptor containing a pyrin domain) inflammasome, which is partly attributable to AMPK inhibition. Conversely, some unsaturated fatty acids are less potent agonists of metabolic inflammation. For example, monounsaturated fatty acid does not reduce AMPK as potently as SFA and n-3 polyunsaturated fatty acids actively resolve inflammation via resolvins and protectins. Nevertheless, the full extent to which nutritional state modulates metabolic inflammation requires greater clarification.
Asunto(s)
Aterosclerosis/etiología , Diabetes Mellitus Tipo 2/etiología , Dieta/efectos adversos , Resistencia a la Insulina , Modelos Inmunológicos , Obesidad/etiología , Adipocitos/inmunología , Adipocitos/metabolismo , Adipocitos/patología , Animales , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Regulación de la Expresión Génica , Humanos , Inflamasomas/inmunología , Inflamasomas/metabolismo , Activación de Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/patologíaRESUMEN
Excessive lipid accumulation in adipose tissue is either the source of obesity or the cause and result of chronic local inflammation, and recent studies indicate that the accumulation may induce many other specialized immunologic features with macrophages and epidemic diseases. We analyze the effective stages of immune cells in adipose tissue, including macrophage recruitment, macrophage polarization, and macrophage-like phenotype preadipocyte possession to find optimal sites as drug targets. Subsequently, some main signaling pathways are summarized in this review, including the AMP-activated protein kinase (AMPK) pathway, the JNK signaling pathway, and a novel one, the Notch signaling pathway. We illustrate all these points in order to determine the general pathogenesis of chronic low-grade local inflammation in adipose tissue and the related signaling pathways. In addition, signal-associated prospective compounds, such as berberine, are summarized and discussed with potential targets in pathogenesis. This might provide some possible thoughts and novel therapies for studying chronic inflammatory diseases, such as insulin resistance and type 2 diabetes mellitus.
Asunto(s)
Adenilato Quinasa/inmunología , Tejido Adiposo/inmunología , Diabetes Mellitus Tipo 2/inmunología , Quinasas Janus/inmunología , Macrófagos/inmunología , Obesidad/inmunología , Adipocitos/inmunología , Animales , Humanos , Inflamación , Terapia Molecular Dirigida , Obesidad/tratamiento farmacológico , Transducción de SeñalRESUMEN
In obesity, gut microbiota LPS may translocate into the blood stream and then contribute to adipose tissue inflammation and oxidative stress, leading to insulin resistance. A causal link between periodontal infection, obesity and type 2 diabetes has also been suggested. We evaluated the ability of polyphenols from Antirhea borbonica medicinal plant to improve the inflammatory and redox status of 3T3-L1 adipocytes exposed to LPS of Porphyromonas gingivalis periodontopathogen or Escherichia coli enterobacteria. Our results show that LPS enhanced the production of Toll-like receptor-dependent MyD88 and NFκB signaling factors as well as IL-6, MCP-1, PAI-1 and resistin. Plant polyphenols reduced LPS pro-inflammatory action. Concomitantly, polyphenols increased the production of adiponectin and PPARγ, known as key anti-inflammatory and insulin-sensitizing mediators. Moreover, both LPS increased intracellular ROS levels and the expression of genes encoding ROS-producing enzymes including NOX2, NOX4 and iNOS. Plant polyphenols reversed these effects and up-regulated MnSOD and catalase antioxidant enzyme gene expression. Noticeably, preconditioning of cells with caffeic acid, chlorogenic acid or kaempferol identified among A. borbonica major polyphenols, led to similar protective properties. Altogether, these findings demonstrate the anti-inflammatory and antioxidant effects of A. borbonica polyphenols on adipocytes, in response to P. gingivalis or E. coli LPS. It will be of major interest to assess A. borbonica polyphenol benefits against obesity-related metabolic disorders such as insulin resistance in vivo.
Asunto(s)
Adipocitos/efectos de los fármacos , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Escherichia coli/inmunología , Lipopolisacáridos/inmunología , Polifenoles/farmacología , Porphyromonas gingivalis/inmunología , Células 3T3-L1 , Adipocitos/inmunología , Adipocitos/microbiología , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Infecciones por Bacteroidaceae/tratamiento farmacológico , Infecciones por Bacteroidaceae/inmunología , Infecciones por Bacteroidaceae/microbiología , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/microbiología , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/microbiología , Ratones , Estrés Oxidativo/efectos de los fármacos , Plantas Medicinales/química , Polifenoles/química , Polifenoles/aislamiento & purificación , Rubiaceae/químicaRESUMEN
Studies have shown that polyphenols reduce the risk of inflammation-related diseases and upregulates energy expenditure in adipose tissue. Here, we investigated the mechanism of the anti-inflammatory and antiobesity effects of almond skin polyphenol extract (ASP) in differentiated 3T3-L1 adipocytes. The antioxidant effects of ASP were measured based on DPPH radical scavenging activity, Trolox equivalent antioxidant capacity, and total phenolic content. Differentiated 3T3-L1 cells were treated with ASP. Subsequently, lipolysis proteins and transcription factors of adipogenesis were measured. The proinflammatory mediators monocyte chemotactic protein-1 (MCP-1) and chemokine ligand 5 (CCL-5) were determined by enzyme-linked immunosorbent assay. We found that ASP significantly promoted phosphorylation of AMP-activated protein kinase (AMPK), increased activity of adipose triglyceride lipase and hormone-sensitive lipase, and inhibited adipogenesis-related transcription factors. In addition, ASP inhibited the tumor necrosis factor-α (TNF-α)-induced cell inflammatory response via downregulation of MCP-1 and CCL-5 secretion. This study suggests that ASP regulates lipolysis through activation of AMPK, reduced adipogenesis, and suppresses proinflammatory cytokines in adipocytes.
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Adipocitos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Lipólisis/efectos de los fármacos , Extractos Vegetales/farmacología , Polifenoles/farmacología , Prunus dulcis/química , Células 3T3-L1 , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/inmunología , Adipocitos/citología , Adipocitos/inmunología , Adipocitos/metabolismo , Animales , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Ratones , Semillas/química , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Sobokchukeo-Tang (ST) is a well-known formula that is used for treating primary dysmenorrhea caused by blood stasis syndrome (BSS) in Korea and China. The current study investigated the antiinflammatory and antiadipogenesis effects of ST on adipocytes and macrophages. The antiinflammatory efficacy of ST was evaluated in RAW 264.7 cells and differentiated THP1 cells. To induce inflammation, the cells were treated with lipopolysaccharide (LPS; 1 µg/ml). Following the induction of inflammation, the levels of proinflammatory cytokines, interleukin6 (IL6) and tumor necrosis factorα (TNFα) in the cell supernatant were detected using enzymelinked immunosorbent assay. 3T3L1 preadipocytes differentiated into adipocytes in response to insulin, isobutyl1methylxanthine and dexamethasone (MDI). To confirm the antiadipogenesis efficacy of ST, we investigated Oil Red O staining was performed, triglyceride (TG) and leptin secretion were measured, and the protein expression of lipid metabolismassociated factors was determined. ST significantly inhibited TNFα and IL6 production in the LPStreated RAW 264.7 cells compared with LPS stimulation alone. In addition, the concentrations of IL6 and TNFα were significantly inhibited by ST in LPStreated THP1 cells. Lipid accumulation was reduced by ST, similarly to the positive control treatment, SB203580. In the STtreated group, the TG and leptin concentrations were inhibited by up to 50 and 83%, respectively, compared with MDI induction only. The STtreated group reduced the protein expression of peroxisome proliferatoractivated receptorγ and CCAAT/enhancerbinding protein α compared with MDI induction only. The results of the present study demonstrated that ST exerts antiinflammatory effects on LPStreated mouse and human macrophage cell lines. ST inhibited adipogenesis in MDIinduced 3T3L1 adipocytes, as indicated by the significant reduction in TG and leptin concentrations without cytotoxicity. Thus, ST may be useful as a therapeutic agent for preventing lipidassociated diseases, including obesity and atherosclerosis.
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Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Antiinflamatorios/farmacología , Medicamentos Herbarios Chinos/farmacología , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Células 3T3-L1 , Adipocitos/inmunología , Adipoquinas/inmunología , Animales , Línea Celular , Humanos , Inflamación/inmunología , Lipogénesis/efectos de los fármacos , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Ratones , Células RAW 264.7RESUMEN
Due to the progressive increase in the incidence of obese and overweight individuals, cardiometabolic syndrome has become a worldwide pandemic in recent years. Given the immunomodulatory properties of riboflavin, the current study was performed to investigate the potency of riboflavin in reducing obesity-related inflammation, which is the main cause of insulin resistance, diabetes mellitus 2 or arteriosclerosis. We determined whether pretreatment with a low dose of riboflavin (10.4-1000 nM) affected the pro-inflammatory activity of adipocyte-macrophage co-culture (3T3 L1-RAW 264.7) following lipopolysaccharide stimulation (LPS; 100 ng/mL) which mimics obesity-related inflammation. The apoptosis of adipocytes and macrophages as well as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1beta (IL-1ß), monocyte chemotactic protein 1 (MCP-1), high-mobility group box 1 (HMGB1), transforming growth factor-beta 1 (TGFß), interleukin 10 (IL-10), inducible nitric oxide synthase (iNOS), nitric oxide (NO), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1) expression and release, macrophage migration and adipokines (adiponectin and leptin) were determined. Our results indicated an efficient reduction in pro-inflammatory factors (TNFα, IL-6, MCP-1, HMGB1) upon culture with riboflavin supplementation (500-1000 nM), accompanied by elevation in anti-inflammatory adiponectin and IL-10. Moreover, macrophage migration was reduced by the attenuation of chemotactic MCP-1 release and degradation of the extracellular matrix by MMP-9. In conclusion, riboflavin effectively inhibits the pro-inflammatory activity of adipocyte and macrophage co-cultures, and therefore we can assume that its supplementation may reduce the likelihood of conditions associated with the mild inflammation linked to obesity.
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Adipocitos/patología , Apoptosis/efectos de los fármacos , Macrófagos/patología , Síndrome Metabólico/prevención & control , Obesidad/patología , Riboflavina/farmacología , Células 3T3-L1 , Adipocitos/citología , Adipocitos/inmunología , Adiponectina/metabolismo , Animales , Línea Celular , Movimiento Celular/efectos de los fármacos , Quimiocina CCL2/metabolismo , Técnicas de Cocultivo , Matriz Extracelular/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Resistencia a la Insulina/fisiología , Interleucina-10/metabolismo , Lipopolisacáridos , Macrófagos/citología , Macrófagos/inmunología , Metaloproteinasa 9 de la Matriz/metabolismo , Síndrome Metabólico/tratamiento farmacológico , RatonesRESUMEN
The interaction between macrophages and adipocytes is known to aggravate inflammation of the adipose tissue, leading to decreased insulin sensitivity. Hence, attenuation of the inflammatory paracrine loop between macrophages and adipocytes is deemed essential to ameliorate insulin resistance and diabetes mellitus type 2. Methyl 2-(4'-methoxy-4'-oxobutanamide) benzoate (compound 1), a newly isolated compound from Jerusalem srtichoke (JA), has not been biologically characterized yet. Here, we investigated whether JA-derived compound 1 attenuates the inflammatory cycle between RAW 264.7 macrophages and 3T3-L1 adipocytes. Compound 1 suppressed the inflammatory response of RAW 264.7 cells to lipopolysaccharide through decreased secretion of IL-1ß, IL-6, and TNF-α. Moreover, the mRNA expression of TNF-α, IL-6, IL-1ß, MCP-1, and Rantes and MAPK pathway activation in 3T3-L1 adipocytes, incubated in macrophage-conditioned media, were inhibited. These findings suggest an anti-inflammatory effect of a newly extracted compound against adipose tissue inflammation and insulin resistance.
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Adipocitos/efectos de los fármacos , Antiinflamatorios/farmacología , Benzoatos/farmacología , Helianthus/química , Macrófagos/efectos de los fármacos , Extractos Vegetales/farmacología , Células 3T3-L1 , Adipocitos/inmunología , Animales , Antiinflamatorios/química , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Macrófagos/inmunología , Ratones , Extractos Vegetales/química , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Mutual interactions between adipocytes and immune cells in white adipose tissue (WAT) are involved in modulation of lipid metabolism in the tissue and also in response to omega-3 polyunsaturated fatty acids (PUFA), which counteract adverse effects of obesity. This complex interplay depends in part on in situ formed anti- as well as pro-inflammatory lipid mediators, but cell types engaged in the synthesis of the specific mediators need to be better characterized. We used tissue fractionation and metabolipidomic analysis to identify cells producing lipid mediators in epididymal WAT of mice fed for 5 weeks obesogenic high-fat diet (lipid content 35% wt/wt), which was supplemented or not by omega-3 PUFA (4.3 mg eicosapentaenoic acid and 14.7 mg docosahexaenoic acid per g of diet). Our results demonstrate selective increase in levels of anti-inflammatory lipid mediators in WAT in response to omega-3, reflecting either their association with adipocytes (endocannabinoid-related N-docosahexaenoylethanolamine) or with stromal vascular cells (pro-resolving lipid mediator protectin D1). In parallel, tissue levels of obesity-associated pro-inflammatory endocannabinoids were suppressed. Moreover, we show that adipose tissue macrophages (ATMs), which could be isolated using magnetic force from the stromal vascular fraction, are not the major producers of protectin D1 and that omega-3 PUFA lowered lipid load in ATMs while promoting their less-inflammatory phenotype. Taken together, these results further document specific roles of various cell types in WAT in control of WAT inflammation and metabolism and they suggest that also other cells but ATMs are engaged in production of pro-resolving lipid mediators in response to omega-3 PUFA.
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Adipocitos/inmunología , Tejido Adiposo Blanco/inmunología , Ácidos Grasos Omega-3/administración & dosificación , Metabolismo de los Lípidos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Adipocitos/efectos de los fármacos , Adipocitos/enzimología , Tejido Adiposo Blanco/citología , Tejido Adiposo Blanco/efectos de los fármacos , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Células Cultivadas , Suplementos Dietéticos , Factores Inmunológicos/inmunología , Metabolismo de los Lípidos/efectos de los fármacos , Macrófagos/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Células del Estroma/efectos de los fármacos , Células del Estroma/inmunologíaRESUMEN
Tocotrienols are unsaturated forms of vitamin E previously shown to reduce adipogenesis and adipose inflammation. In this study, muscadine grape seed oil (MGSO) was identified as a novel source of tocotrienols containing significant amounts of α- and γ-tocotrienol (T3) with minor seasonal changes. The aim of this study was to assess the anti-adipogenic and anti-inflammatory potential of MGSO by using primary human adipose-derived stem cells (hASCs). Differentiating hASCs were treated with MGSO and compared with rice bran and olive oil. Accumulation of triglyceride was significantly lower in MGSO-treated hASCs than rice bran and olive oils. A tocotrienol rich fraction (TRF) from MGSO was prepared by solid phase extraction and eluted with 15% 1,4-dioxane in hexane. The MGSO-derived TRF treatment significantly reduced mRNA and protein expression that are crucial to adipogenesis (e.g., PPARγ and aP2) in hASCs. Furthermore, TRF from MGSO markedly reduced LPS-induced proinflammatory gene expression in human adipocytes and cytokine secretion to the medium (IL-6 and IL-8). Collectively, our work suggests that MGSO is a stable and reliable natural source of T3 and MGSO may constitute a new dietary strategy to attenuate obesity and its associated adipose inflammation.
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Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Antiinflamatorios/farmacología , Aceites de Plantas/farmacología , Tocotrienoles/farmacología , Vitis/química , Adipocitos/citología , Adipocitos/inmunología , Humanos , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , PPAR gamma/genética , PPAR gamma/inmunología , Semillas/químicaRESUMEN
Obesity is characterized by an increase in the infiltration of monocytes into the adipose tissue, causing an inflammatory condition associated with, for example, the development of insulin resistance. Thus, anti-inflammatory-based treatments could emerge as a novel and interesting approach. It has been reported that Chilean native fruits maqui (Aristotelia chilensis) and calafate (Berberis microphylla) present high contents of polyphenols, which are known for their antioxidant and anti-inflammatory properties. The aim of this study was to evaluate the ability of extracts of these fruits to block the pathogenic interaction between adipocytes and macrophages in vitro and to compare its effect with blueberry (Vaccinium corymbosum) extract treatment, which has been already described to possess several biomedical benefits. RAW264.7 macrophages were treated with 5 µg/mL lipopolysaccharides (LPS), with conditioned media (CM) from fully differentiated 3T3-L1 adipocytes, or in a coculture (CC) with 3T3-L1 adipocytes, in the presence or absence of 100 µM [total polyphenolic content] of each extract for 24 h. The gene expression and secretion profile of several inflammatory markers were evaluated. Nitric oxide secretion induced by LPS, CM, and CC was reduced by the presence of maqui (-12.2%, -45.6%, and -14.7%, respectively) and calafate (-27.6%, -43.9%, and -11.8%, respectively) extracts. Gene expression of inducible nitric oxide synthase and TNF-α was inhibited and of IL-10 was induced by maqui and calafate extract incubation. In conclusion, the extracts of these fruits present important inhibitory-like features over the inflammatory response of the interaction between adipocytes and macrophages, comprising a potential therapeutic tool against comorbidities associated with obesity development.
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Adipocitos/efectos de los fármacos , Berberis/química , Elaeocarpaceae/química , Inflamación/inmunología , Macrófagos/efectos de los fármacos , Extractos Vegetales/farmacología , Células 3T3-L1 , Adipocitos/inmunología , Animales , Chile , Frutas/química , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Interleucina-10/genética , Interleucina-10/inmunología , Macrófagos/inmunología , Ratones , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Obesity-associated low-grade inflammation of white adipose tissue (WAT) contributes to development of insulin resistance and other disorders. Accumulation of immune cells, especially macrophages, and macrophage polarization from M2 to M1 state, affect intrinsic WAT signaling, namely anti-inflammatory and proinflammatory cytokines, fatty acids (FA), and lipid mediators derived from both n-6 and n-3 long-chain PUFA such as (i) arachidonic acid (AA)-derived eicosanoids and endocannabinoids, and (ii) specialized pro-resolving lipid mediators including resolvins derived from both eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), lipoxins (AA metabolites), protectins and maresins (DHA metabolites). In this respect, potential differences in modulating adipocyte metabolism by various lipid mediators formed by inflammatory M1 macrophages typical of obese state, and non-inflammatory M2 macrophages typical of lean state remain to be established. Studies in mice suggest that (i) transient accumulation of M2 macrophages could be essential for the control of tissue FA levels during activation of lipolysis, (ii) currently unidentified M2 macrophage-borne signaling molecule(s) could inhibit lipolysis and re-esterification of lipolyzed FA back to triacylglycerols (TAG/FA cycle), and (iii) the egress of M2 macrophages from rebuilt WAT and removal of the negative feedback regulation could allow for a full unmasking of metabolic activities of adipocytes. Thus, M2 macrophages could support remodeling of WAT to a tissue containing metabolically flexible adipocytes endowed with a high capacity of both TAG/FA cycling and oxidative phosphorylation. This situation could be exemplified by a combined intervention using mild calorie restriction and dietary supplementation with EPA/DHA, which enhances the formation of "healthy" adipocytes. This article is part of a Special Issue entitled Oxygenated metabolism of PUFA: analysis and biological relevance."
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Tejido Adiposo Blanco/metabolismo , Inflamación/metabolismo , Metabolismo de los Lípidos , Obesidad/metabolismo , Transducción de Señal , Adipocitos/inmunología , Adipocitos/metabolismo , Tejido Adiposo Blanco/inmunología , Animales , Comunicación Celular , Metabolismo Energético , Humanos , Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Metabolismo de los Lípidos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Obesidad/inmunologíaRESUMEN
With the steady rise in the incidence of obesity and its associated comorbidities, in the last decades research aimed at understanding molecular mechanisms that control body weight has gained new interest. Fat gain is frequently associated with chronic adipose tissue inflammation and with peripheral as well as central metabolic derangements, resulting in an impaired hypothalamic regulation of energy homeostasis. Recent attention has focused on the role of phosphatidylinositol 3-kinase (PI3K) in both immune and metabolic response pathways, being involved in the pathophysiology of obesity and its associated metabolic diseases. In this review, we focus on distinct PI3K isoforms, especially class I PI3Ks, mediating inflammatory cells recruitment to the enlarged fat as well as intracellular responses to key hormonal regulators of fat storage, both in adipocytes and in the central nervous system. This integrated view of PI3K functions may ultimately help to develop new therapeutic interventions for the treatment of obesity.