RESUMEN
Cytomegalovirus (CMV) infection poses risks to newborns, necessitating effective therapies. Given that the damage includes both viral infection of brain cells and immune system-related damage, here we investigate the involvement of cellular prion protein (PrP), which plays vital roles in neuroprotection and immune regulation. Using a murine model, we show the role of PrP in tempering neonatal T cell immunity during CMV infection. PrP-null mice exhibit enhanced viral control through elevated virus-specific CD8 T cell responses, leading to reduced viral titers and pathology. We further unravel the molecular mechanisms by showing CMV-induced upregulation followed by release of PrP via the metalloproteinase ADAM10, impairing CD8 T cell response specifically in neonates. Additionally, we confirm PrP downregulation in human CMV (HCMV)-infected fibroblasts, underscoring the broader relevance of our observations beyond the murine model. Furthermore, our study highlights how PrP, under the stress of viral pathogenesis, reveals its impact on neonatal immune modulation.
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Animales Recién Nacidos , Linfocitos T CD8-positivos , Infecciones por Citomegalovirus , Citomegalovirus , Ratones Noqueados , Animales , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Citomegalovirus/inmunología , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Femenino , Fibroblastos/metabolismo , Fibroblastos/virología , Proteínas Priónicas/metabolismo , Proteínas Priónicas/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Proteína ADAM10/metabolismo , Proteína ADAM10/genéticaRESUMEN
Several inflammatory markers such as cytokines, chemokines, and microRNAs (miRNAs) are well known to be induced during obesity and are strongly linked to their comorbidities. Among many others factors, the micronutrient status is suspected to reduce obesity-associated inflammation via blunting inflammatory signalling pathways. This is notably the case for active forms of vitamin A (all-trans retinoic acid ATRA) and vitamin D (1,25(OH)2D) as previously shown. In the present study, we aimed to implement a new bioinformatics approach to unveil commonly regulated signalling pathways through a combination of gene and miRNA expression sets impacted by ATRA and 1,25(OH)2D in adipocytes. In a first set of experiments, we focused only our attention on ATRA and demonstrated that it reduced LPS-mediated miRNA expression (miR-146a, miR-150, and miR-155) in mouse adipose tissue, in adipocyte cultures, and in adipocyte-derived vesicles. This result was confirmed in TNFα-induced miRNA in human adipocytes. Then, bioinformatic analysis highlighted that both ATRA and 1,25(OH)2D-regulated genes and miRNA converge to the canonical 'nuclear factor Kappa B (NF-κB) signalling pathway.' Altogether, these results showed that ATRA has anti-inflammatory effects on miRNA expression. In addition, the proposed bioinformatic model converges to NF-κB signalling pathway that has been previously demonstrated to be regulated by ATRA and 1,25(OH)2D, thus confirming the interest of such approach.
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MicroARNs , FN-kappa B , Animales , Ratones , Humanos , FN-kappa B/metabolismo , Metilación de ADN , Adipocitos/metabolismo , Tretinoina/farmacología , MicroARNs/genética , MicroARNs/metabolismo , Obesidad/genéticaRESUMEN
Long-term multilineage hematopoietic donor chimerism occurs sporadically in patients who receive a transplanted solid organ enriched in lymphoid tissues such as the intestine or liver. There is currently no evidence for the presence of kidney-resident hematopoietic stem cells in any mammal species. Graft-versus-host-reactive donor T cells promote engraftment of graft-derived hematopoietic stem cells by making space in the bone marrow. Here, we report full (over 99%) multilineage, donor-derived hematopoietic chimerism in a pediatric kidney transplant recipient with syndromic combined immune deficiency that leads to transplant tolerance. Interestingly, we found that the human kidney-derived hematopoietic stem cells took up long-term residence in the recipient's bone marrow and gradually replaced their host counterparts, leading to blood type conversion and full donor chimerism of both lymphoid and myeloid lineages. Thus, our findings highlight the existence of human kidney-derived hematopoietic stem cells with a self-renewal ability able to support multilineage hematopoiesis.
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Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas , Animales , Humanos , Niño , Médula Ósea , Linfocitos T , Hematopoyesis , Riñón , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Médula Ósea , MamíferosRESUMEN
Propolis extracts are considered as nutraceutical products with potentialities towards obesity and comorbidities management. Nevertheless, propolis extracts composition is highly variable and depends on the botanic origin of plants used by the bees to produce propolis. This study aims to evaluate the differential effect of poplar propolis extract powder (PPEP), Baccharis propolis extract powder (BPEP), and/ or Dalbergia propolis extract powder (DPEP) on obesity and glucose homeostasis in high-fat-fed mice. PPEP supplementation reduced high-fat (HF)-mediated body weight gain, adiposity index, and improved glucose homeostasis in male C57Bl/6J mice that were submitted to a high-fat diet for 12 weeks, whereas BPEP, DPEP, or a mix of the three PEPs did not modify those parameters. Adipose tissue (AT) gene expression profiling highlighted an induction of mRNA related to lipid catabolism and an inhibition of mRNA coding for inflammatory markers. Several Nrf2 target genes, coding for antioxidant enzymes, were induced in AT under PPEP effect, but not by other PEP. Interestingly, representative PPEP polyphenols mediated the induction of Nrf2 target genes cell-autonomously in adipocytes, suggesting that this induction may be related to the specific polyphenol content of PPEP. Whereas PPEP supplementation has demonstrated a clear potential to blunt the onset of obesity and associated comorbidities, other PEPs (from Baccharis and Dalbergia) were inefficient to support their role in preventive nutrition.
RESUMEN
Obesity is classically associated with low serum total and free 25(OH)D. Hypotheses have been advanced to explain this observation but mechanisms remain poorly understood, and notably priming events that could explain such association. We investigated the impact of short-term high fat (HF) diet to investigate early events occurring in vitamin D metabolism. Male C57BL/6J mice were fed with a control diet (control group) and HF diet for 4 days. HF fed mice displayed similar body weight to control mice but significantly increased adiposity, together with a decrease of free 25(OH)D concentrations, which could be explained at least in part by a decrease of Cyp2r1 and Cyp3a11 expression in the liver. An increase of 1,25(OH)2D concentration was also observed and could be explained by a decrease of Cyp24a1 expression observed in the kidney. In white adipose tissue (WAT), no modification of vitamin D metabolites quantity detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Nevertheless, an increase of Cyp2r1 and Cyp27a1 mRNA expression and a decrease of Cyp27b1 mRNA expression could suggest a possible storage of 25(OH)D in WAT at long-term. Our data are supportive of an active role of HF diet in mediating a priming effect leading the well-established perturbation of the vitamin D metabolism associated with obesity, including a decrease of free 25(OH)D and modulation of expression of genes involved in vitamin D metabolism.
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Dieta Alta en Grasa/efectos adversos , Obesidad/enzimología , Vitamina D/análogos & derivados , Tejido Adiposo Blanco/enzimología , Animales , Colecalciferol/sangre , Perfilación de la Expresión Génica , Riñón/enzimología , Hígado/enzimología , Masculino , Ratones Endogámicos C57BL , Obesidad/etiología , Vitamina D/metabolismoAsunto(s)
COVID-19 , Citocinas , Humanos , Inflamación/tratamiento farmacológico , Pronóstico , SARS-CoV-2RESUMEN
SCOPE: Current evidence supports the beneficial effect of polyphenols on the management of obesity and associated comorbidities. This is the case for propolis, a polyphenol-rich substance produced by bees. The aim of the present study is to evaluate the effect of a poplar propolis ethanolic extract (PPEE) on obesity and glucose homeostasis, and to unveil its putative molecular mechanisms of action. METHODS AND RESULTS: Male high-fat (HF) diet-fed mice are administered PPEE for 12 weeks. PPEE supplementation reduces the HF-mediated adiposity index, adipocyte hypertrophy, and body weight gain. It also improves HOMA-IR and fasting glucose levels. Gene expression profiling of adipose tissue (AT) shows an induction of mRNA related to lipid catabolism and mitochondrial biogenesis and inhibition of mRNA coding for inflammatory markers. Interestingly, several Nrf2-target genes are induced in AT following administration of PPEE. The ability of PPEE to induce the expression of Nrf2-target genes is studied in adipocytes. PPEE is found to transactivate the Nrf2 response element and the Nrf2 DNA-binding, suggesting that part of the effect of PPEE can be mediated by Nrf2. CONCLUSION: PPEE supplementation may represent an interesting preventive strategy to tackle the onset of obesity and associated metabolic disorders.
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Tejido Adiposo/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Glucosa/metabolismo , Obesidad/prevención & control , Própolis/farmacología , Células 3T3-L1 , Tejido Adiposo/fisiología , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Etanol/química , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Obesidad/etiología , Extractos Vegetales/química , Polifenoles/análisis , Populus , Própolis/química , Aumento de Peso/efectos de los fármacosRESUMEN
OBJECTIVE: This study aimed to determine the effects of physical exercise on the angio-adaptive response in adipose tissue following weight loss in a mouse model of diet-induced obesity. We hypothesized that physical exercise stimulates angiogenesis through the regulation of Vascular endothelial growth factor-A (VEGF-A) pro-/Thrombospondin-1 (TSP-1) anti-angiogenic signal under the control of the Murine double-minute 2/Forkhead box Os (Mdm2/FoxOs) axis, as reported in skeletal muscle. METHODS: We studied the effects of 7â¯weeks-voluntary exercise (Ex) in C57Bl/6 control or diet-induced obese (HFS) mice on vascularization of white adipose tissue (AT). RESULTS: Diet-induced obese sedentary (HFSsed) mice presented a powerful angiostatic control in all adipose tissues, under FoxOs protein regulation, leading to capillary rarefaction. Exercise increased expression of Mdm2, repressing the angiostatic control in favor of adipose vascular regrowth in normal chow (NCex) and HFSex mice. This phenomenon was associated with adipocytes microenvironment improvement, such as decreased adipocytes hypertrophy and adipose tissue inflammation. In addition, adipose angiogenesis stimulation by exercise through Mdm2 pro-angiogenic action, improved visceral adipose insulin sensitivity, activated browning process within subcutaneous adipose tissue (ScWAT) and decreased ectopic fat deposition (muscle, heart and liver) in obese HFSex mice. The overall result of this approach of therapy by physical exercise is an improvement of all systemic cardiometabolic parameters. CONCLUSIONS: These data demonstrated the therapeutic efficacy of physical exercise against obesity-associated pathologies, and also offer new prospects for molecular therapies targeting the adipose angio-adaptation in obese humans.
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Adipocitos Blancos/metabolismo , Tejido Adiposo Blanco/irrigación sanguínea , Tejido Adiposo Blanco/metabolismo , Dieta Alta en Grasa , Terapia por Ejercicio , Neovascularización Fisiológica , Obesidad/terapia , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Adipocitos Marrones/metabolismo , Adipocitos Marrones/patología , Adipocitos Blancos/patología , Tejido Adiposo Blanco/patología , Animales , Microambiente Celular , Modelos Animales de Enfermedad , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O3/metabolismo , Masculino , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/patología , Obesidad/fisiopatología , Transducción de Señal , Trombospondina 1/metabolismo , Técnicas de Cultivo de Tejidos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Pérdida de PesoRESUMEN
Women with low levels of vitamin D have a higher risk of developing breast cancer. Numerous studies associated the presence of a CD8+ T cell infiltration with a good prognosis. As vitamin D may play a key role in the modulation of the immune system, the objective of this work was to evaluate the impact of vitamin D on the breast cancer progression and mammary tumor microenvironment. We show that vitamin D decreases breast cancer tumor growth. Immunomonitoring of the different immune subsets in dissociated tumors revealed an increase in tumor infiltrating CD8+ T cells in the vitamin D-treated group. Interestingly, these CD8+ T cells exhibited a more active T cell (TEM/CM) phenotype. However, in high-fat diet conditions, we observed an opposite effect of vitamin D on breast cancer tumor growth, associated with a reduction of CD8+ T cell infiltration. Our data show that vitamin D is able to modulate breast cancer tumor growth and inflammation in the tumor microenvironment in vivo. Unexpectedly, this effect is reversed in high-fat diet conditions, revealing the importance of diet on tumor growth. We believe that supplementation with vitamin D can in certain conditions represent a new adjuvant in the treatment of breast cancers.
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Neoplasias de la Mama/inmunología , Linfocitos T CD8-positivos/inmunología , Vitamina D/inmunología , Animales , Neoplasias de la Mama/patología , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Proliferación Celular/fisiología , Progresión de la Enfermedad , Femenino , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Ratones , Ratones Endogámicos C57BL , Pronóstico , Microambiente Tumoral/inmunologíaRESUMEN
SCOPE: Although about 90% of lycopene in dietary sources occurs in the linear all-trans conformation, a large proportion of the lycopene found in human tissues is of the cis-isomer type, notably (5Z)-lycopene. The biological effects of this (5Z) isomer have been under-researched. The aim of this study is to evaluate some biological functions of (5Z)-lycopene in adipocytes and to compare them with those of (all-E)-lycopene. METHODS AND RESULTS: (all-E)- and (5Z)-Lycopene displayed strong similarities in global gene expression profile and biological pathways impacted. Peroxisome proliferator-activated receptor (PPAR) signaling is identified as a major actor mediating the effects of lycopene isomers. Transactivation assays confirmed the ability of both isomers to transactivate PPARγ. In addition, the TNFα-induced proinflammatory cytokine mRNA expression in 3T3-L1 adipocytes is reduced by both isomers via a reduction in the phosphorylation levels of p65. Finally, lycopene isomers restore the TNF-α-blunted uptake of glucose by adipocytes via a modulation of AKT phosphorylation. CONCLUSION: These results show that lycopene isomers exert similar biological functions in adipocytes, linked to their ability to transactivate PPARγ. These findings add to our knowledge of lycopene effects in adipocyte biology and point to the possible use of lycopene in the prevention of obesity-related disorders.
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Adipocitos/efectos de los fármacos , Adipocitos/fisiología , Licopeno/química , Licopeno/farmacología , Células 3T3-L1 , Animales , Citocinas/metabolismo , Desoxiglucosa/farmacocinética , Regulación de la Expresión Génica/efectos de los fármacos , Isomerismo , Ratones , FN-kappa B/metabolismo , PPAR gamma/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Low circulating levels of total and free 25-hydroxyvitamin D (25(OH)D) indicative of vitamin D status have been associated with obesity in humans. Moreover, obesity is thought to play a causal role in the reduction of 25(OH)D levels, and several theories have been put forward to explain this relationship. Here we tested the hypothesis that obesity disrupts vitamin D homeostasis in key organs of vitamin D metabolism. Male C57BL6 mice were fed for 7 or 11 weeks on either a control diet (control, 10% energy from fat) or a high-fat diet (HF, 60% energy from fat) formulated to provide equivalent vitamin D3 intake in both groups. After 7 weeks, there was a transient increase of total 25(OH)D together with a significant decrease of plasma vitamin D3 that could be related to the induction of hepatic genes involved in 25-hydroxylation. After 11 weeks, there was no change in total 25(OH)D but a significant decrease of free 25(OH)D and plasma vitamin D3 levels. We also quantified an increase of 25(OH)D in adipose tissue that was inversely correlated to the free 25(OH)D. Interestingly, this accumulation of 25(OH)D in adipose tissue was highly correlated to the induction of Cyp2r1, which could actively participate in vitamin D3 trapping and subsequent conversion to 25(OH)D in adipose tissue. Taken together, our data strongly suggest that the enzymes involved in vitamin D metabolism, notably in adipose tissue, are transcriptionally modified under high-fat diet, thus contributing to the obesity-related reduction of free 25(OH)D.
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Tejido Adiposo/metabolismo , Dieta Alta en Grasa/efectos adversos , Regulación de la Expresión Génica/fisiología , Obesidad/patología , Vitamina D/análogos & derivados , Animales , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Vitamina D/administración & dosificación , Vitamina D/sangre , Vitamina D/metabolismoRESUMEN
OBJECTIVE: This study aimed to explore the role of nine microRNAs (miRNAs) in microparticles (MPs) on the efficacy of aerobic exercise in the regulation of inflammation and vascular function in obesity. METHODS: Sedentary women with normal weight (n = 6, BMI < 25 kg/m2 ) and women with obesity (n = 9, BMI > 30 kg/m2 ) were recruited at F. Hached Hospital (Sousse, Tunisia) and enrolled in an 8-week aerobic program. Vascular function was assessed using laser Doppler flowmetry/iontophoresis, circulating MPs by flow cytometry, miRNAs by real-time polymerase chain reaction, and inflammation by ELISA, before and after exercise. RESULTS: Women with obesity presented with high prevalence of cardiovascular risk factors and a higher circulating MP level compared with healthy subjects. The MP miRNA profile was significantly different in the two groups. Exercise reduced BMI and inflammation in both groups and significantly improved endothelial-dependent response (acetylcholine cutaneous vascular conductance) for healthy subjects, with a trend for women with obesity. Circulating MP level was increased after exercise, and miRNA expression was differentially modulated in both populations. Pearson analysis revealed a correlation between MPs miR-124a and miR150 and adiponectin, TNFα, or IL-6 levels. CONCLUSIONS: The relation between MPs and miRNA profile, inflammation, vascular function, and exercise is of particular interest for defining "miRNA biomarker signature" in patients with cardiovascular disease who are potentially susceptible to respond to exercise.
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Biomarcadores/metabolismo , Enfermedades Cardiovasculares/metabolismo , Ejercicio Físico/fisiología , Inflamación/metabolismo , MicroARNs/genética , Obesidad/metabolismo , Adulto , Micropartículas Derivadas de Células/metabolismo , Femenino , Humanos , Obesidad/terapia , Adulto JovenRESUMEN
It is well established that the active form of vitamin D (i.e., 1,25-dihydroxyvitamin D [1,25(OH)2D]) regulates the expression of genes involved in its own metabolism and transport in the kidney and possibly in the liver. However, little is known about the transcriptional impact of cholecalciferol supplementation on white adipose tissue (WAT) and adipocytes, which are a major site of vitamin D and 25-hydroxyvitamin D [25(OH)D] storage in the organism. To fill this gap, we investigated the impact of cholecalciferol supplementation in WAT via a panel of genes coding for enzymes and proteins involved in vitamin D metabolism and uptake. Mice supplemented with cholecalciferol (15,000 IU/kg of body weight per day) for 4 days showed decreased messenger RNA (mRNA) levels of proteins involved in cholecalciferol metabolism (Cyp24a1, Cyp27a1) and decreased cubilin mRNA levels in WAT. These data were partly confirmed in 3T3-L1 adipocytes incubated with 1,25(OH)2D. The downregulation of cubilin mRNA observed in WAT and in 3T3-L1 was confirmed at the protein level in WAT and at the mRNA level in human primary adipocytes. Vitamin D receptor (VDR) agonist (EB1089) and RNA interference approaches demonstrated that VDR was involved in this regulation. Furthermore, chemical inhibitor and RNA inference analysis demonstrated that cubilin was involved in 25(OH)D uptake by adipocytes. This study established an overall snapshot of the genes regulated by cholecalciferol in mouse WAT and cell-autonomously in adipocytes. We highlighted that the regulation of cubilin expression was mediated by a VDR-dependent mechanism, and we demonstrated that cubilin was involved in 25(OH)D uptake by adipocytes.
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Adipocitos/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Colecalciferol/farmacología , Receptores de Superficie Celular/genética , Vitamina D/análogos & derivados , Células 3T3-L1 , Adipocitos/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Células Cultivadas , Suplementos Dietéticos , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Receptores de Superficie Celular/metabolismo , Vitamina D/farmacocinéticaRESUMEN
Inflammation of adipose tissue is believed to be a contributing factor to many chronic diseases associated with obesity. Vitamin D (VD) is now known to limit this metabolic inflammation by decreasing inflammatory marker expression and leukocyte infiltration in adipose tissue. In this study, we investigated the impact of VD on microRNA (miR) expression in inflammatory conditions in human and mouse adipocytes, using high-throughput methodology (miRNA PCR arrays). Firstly, we identified three miRs (miR-146a, miR-150, and miR-155) positively regulated by TNFα in human adipocytes. Interestingly, the expression of these miRs was strongly prevented by 1,25(OH)2D preincubation. These results were partly confirmed in 3T3-L1 adipocytes (for miR-146a and miR-150). The ability of VD to control the expression of these miRs was confirmed in diet-induced obese mice: the levels of the three miRs were increased following high fat (HF) diet in epididymal white adipose tissue and reduced in HF diet fed mice supplemented with VD. The involvement of NF-κB signaling in the induction of these miRs was confirmed in vitro and in vivo using aP2-p65 transgenic mice. Finally, the ability of VD to deactivate NF-κB signaling, via p65 and IκB phosphorylation inhibition in murine adipocyte, was observed and could constitute a driving molecular mechanism. This study demonstrated for the first time that VD modulates the expression of miRs in adipocytes in vitro and in adipose tissue in vivo through its impact on NF-κB signaling pathway, which could represent a new mechanism of regulation of inflammation by VD.
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Adipocitos/metabolismo , Antiinflamatorios/farmacología , MicroARNs/genética , Vitamina D/farmacología , Vitaminas/farmacología , Células 3T3 , Adipocitos/efectos de los fármacos , Animales , Células Cultivadas , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
SCOPE: Several studies have linked the high intake of lycopene or tomatoes products with lower risk for metabolic diseases. The aim of the present study was to evaluate and to compare the effect of lycopene and tomato powder on obesity-associated disorders. METHODS AND RESULTS: Male C57BL/J6 mice were assigned into four groups to receive: control diet (CD), high fat diet (HFD), high fat diet supplemented with lycopene or with tomato powder (TP) for 12 weeks. In HFD condition, lycopene and TP supplementation significantly reduced adiposity index, organ, and relative organ weights, serum triglycerides, free fatty acids, 8-iso-prostaglandin GF2α and improved glucose homeostasis, but did not affect total body weight. Lycopene and TP supplementation prevented HFD-induced hepatosteatosis and hypertrophy of adipocytes. Lycopene and TP decreased HFD-induced proinflammatory cytokine mRNA expression in the liver and in the epididymal adipose tissue. The anti-inflammatory effect of lycopene and TP was related to a reduction in the phosphorylation levels of IκB, and p65, and resulted in a decrease of inflammatory proteins in adipose tissue. CONCLUSION: These results suggest that lycopene or TP supplementation display similar beneficial health effects that could be particularly relevant in the context of nutritional approaches to fight obesity-associated pathologies.
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Antiinflamatorios/farmacología , Carotenoides/farmacología , Enfermedades Metabólicas/tratamiento farmacológico , Obesidad/prevención & control , Solanum lycopersicum , Tejido Adiposo/metabolismo , Animales , Composición Corporal/efectos de los fármacos , Dieta Alta en Grasa , Suplementos Dietéticos , Metabolismo de los Lípidos , Licopeno , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/fisiologíaRESUMEN
An effect of the Vitamin A metabolite all-trans-retinoic acid (ATRA) on body weight regulation and adiposity has been described, but little is known about its impact on obesity-associated inflammation. Our objective was to evaluate the overall impact of this metabolite on inflammatory response in human and mouse adipocytes, using high-throughput methods, and to confirm its effects in a mouse model. ATRA (2 µM for 24 h) down-regulated the mRNA expression of 17 chemokines in human adipocytes, and limited macrophage migration in a TNFα-conditioned 3 T3-L1 adipocyte medium (73.7%, P<.05). These effects were confirmed in mice (n=6-9 per group) subjected to oral gavage of ATRA (5 mg/kg of body weight) and subsequently injected intraperitoneally with lipopolysaccharide. In this model, both systemic and adipose levels of inflammatory markers were reduced. The antiinflammatory effect of ATRA was associated with a reduction in the phosphorylation levels of IκB and p65 (~50%, P<.05), two subunits of the NF-κB pathway, probably mediated by PGC1α, in 3 T3-L1 adipocytes. Taken together, these results show a significant overall antiinflammatory effect of ATRA on proinflammatory cytokine and chemokine production in adipocyte and adipose tissue and suggest that ATRA supplementation may represent a strategy of preventive nutrition to fight against obesity and its complications.
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Adipocitos/efectos de los fármacos , Quimiocinas/metabolismo , FN-kappa B/metabolismo , Tretinoina/farmacología , Células 3T3-L1 , Adipocitos/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Suplementos Dietéticos , Humanos , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Paniculitis/tratamiento farmacológico , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Transducción de Señal/efectos de los fármacos , Transcriptoma/efectos de los fármacosRESUMEN
Adiponectin is an adipocyte-derived adipokine with potent antidiabetic, anti-inflammatory, and antiatherogenic activity. Long-term, high-fat diet results in gain of body weight, adiposity, further inflammatory-based cardiovascular diseases, and reduced adiponectin secretion. Vitamin A derivatives/retinoids are involved in several of these processes, which mainly take place in white adipose tissue (WAT). In this study, we examined adiponectin expression as a function of dietary high-fat and high-vitamin A conditions in mice. A decrease of adiponectin expression in addition to an up-regulation of aldehyde dehydrogenase A1 (ALDH1A1), retinoid signaling, and retinoic acid response element signaling was selectively observed in WAT of mice fed a normal-vitamin A, high-fat diet. Reduced adiponectin expression in WAT was also observed in mice fed a high-vitamin A diet. Adipocyte cell culture revealed that endogenous and synthetic retinoic acid receptor (RAR)α- and RARγ-selective agonists, as well as a synthetic retinoid X receptor agonist, efficiently reduced adiponectin expression, whereas ALDH1A1 expression only increased with RAR agonists. We conclude that reduced adiponectin expression under high-fat dietary conditions is dependent on 1) increased ALDH1A1 expression in adipocytes, which does not increase all-trans-retinoic acid levels; 2) further RAR ligand-induced, WAT-selective, increased retinoic acid response element-mediated signaling; and 3) RAR ligand-dependent reduction of adiponectin expression.-Landrier, J.-F., Kasiri, E., Karkeni, E., Mihály, J., Béke, G., Weiss, K., Lucas, R., Aydemir, G., Salles, J., Walrand, S., de Lera, A. R., Rühl, R. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue.
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Adiponectina/metabolismo , Aldehído Deshidrogenasa/metabolismo , Dieta Alta en Grasa/efectos adversos , Regulación de la Expresión Génica/fisiología , Receptores de Ácido Retinoico/metabolismo , Células 3T3-L1 , Adipocitos/fisiología , Adiponectina/genética , Tejido Adiposo/fisiología , Aldehído Deshidrogenasa/genética , Familia de Aldehído Deshidrogenasa 1 , Alcaloides , Alimentación Animal/análisis , Animales , Suplementos Dietéticos , Regulación hacia Abajo/fisiología , Masculino , Ratones , Ratones Noqueados , Obesidad , Oxindoles , Receptores de Ácido Retinoico/genética , Retinal-Deshidrogenasa , Transducción de Señal/fisiología , Tretinoina/metabolismo , Regulación hacia Arriba , Vitamina A/administración & dosificaciónRESUMEN
CONTEXT: Obesity alters adipose tissue's metabolic and endocrine functions and causes a chronic local and systemic low-grade inflammatory state to develop, generating obesity-associated complications. In the last decade, many entities contributing to and regulating this inflammatory state have been identified, among which are microRNAs. OBJECTIVE: This study aimed to identify microRNA regulated in inflamed adipocytes and adipose tissue, and its effect on adipocyte biology. DESIGN AND RESULTS: We screened the expression profile of TNFα-treated adipocytes (a major pro-inflammatory protein expressed in obese adipose tissue), and identified miR-155 as the most responsive microRNA. The involvement of TNFα on the basal miR-155 expression was confirmed in the adipose tissue of Tnfa−/− mice where miR-155 was significantly reduced. Also, mice overexpressing p65 or invalidated for p65 in adipose tissue respectively increased and decreased miR-155 expression, in line with the involvement of the nuclear factor κB (NF-κB) pathway in miR-155 induction. miR-155 expression was higher in obese subjects' adipose tissue than in that of normal-weight subjects, and correlated with TNFα expression and body mass index. Gain and loss of function of miR-155 showed its effect on adipocyte function, probably via its ability to target PPARγ mRNA 3'UTR. Interestingly, miR-155 overexpression also resulted in an increased inflammatory state in adipocytes. CONCLUSION: Altogether, these data are evidence of a proinflammatory loop mediated by NF-κB and miR-155 that could participate in the amplification of inflammatory status in adipocytes.
Asunto(s)
Adipocitos/patología , Tejido Adiposo/patología , Inflamación/etiología , MicroARNs/genética , Obesidad/complicaciones , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Adulto , Animales , Células Cultivadas , Humanos , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de SeñalRESUMEN
Cross-sectional studies depict an inverse relationship between vitamin D (VD) status reflected by plasma 25-hydroxy-vitamin D and obesity. Furthermore, recent studies in vitro and in animal models tend to demonstrate an impact of VD and VD receptor on adipose tissue and adipocyte biology, pointing to at least a part-causal role of VD insufficiency in obesity and associated physiopathological disorders such as adipose tissue inflammation and subsequent insulin resistance. However, clinical and genetic studies are far less convincing, with highly contrasted results ruling out solid conclusions for the moment. Nevertheless, prospective studies provide interesting data supporting the hypothesis of a preventive role of VD in onset of obesity. The aim of this review is to summarise the available data on relationships between VD, adipose tissue/adipocyte physiology, and obesity in order to reveal the next key points that need to be addressed before we can gain deeper insight into the controversial VD-obesity relationship.
RESUMEN
Vitamin D (VD) displays immunoregulatory effects and reduces adipocyte inflammation, which may participate to a reduction of adipose tissue macrophage infiltration in the context of obesity-associated low-grade inflammation. These observations have been described mainly in vitro, through the evaluation of a limited number of inflammatory markers. Here, we studied the effects of 1,25 dihydroxy-VD on chemokine network expression in adipocytes (by transcriptomic approach), and we confirm the physiological relevance of these data in vivo, by demonstrating the effect of VD on cytokine and chemokine gene expression as well as on macrophage infiltration in adipose tissue. 1,25 dihydroxy-VD down-regulated (-1.3- to -10.8-fold) the mRNA expression of 29 chemokines and limited macrophage migration in TNFα-conditioned adipocyte medium (1.5-fold; P < .05). This effect was associated with a reduction in p65 and IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) phosphorylation (2-fold compared with TNFα; P < .05). The effects of VD were confirmed in mice injected ip with lipopolysaccharide (acute inflammation) and diet-induced obese mice (metabolic inflammation), where the levels of mRNA encoding proinflammatory cytokines and chemokines (â¼2-fold) were reduced in adipocytes (acute and metabolic inflammation) and adipose tissue and that macrophage infiltration was also inhibited in the adipose tissue of obese mice (metabolic inflammation). Altogether, these results showed that VD displayed a global immunoregulatory impact on adipocytes, notably via the inhibition of chemokine expression and macrophage infiltration in inflamed adipose tissue.