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International audience; 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.

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.

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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.

International audience; 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.

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 7 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.

International audience; 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.

International audience; 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.

The endocrine system is a network of glands that produces and releases hormones, which helps to control many important body functions. The diseases associated with the endocrine system may result from a dysfunction at different levels during release or action of the hormones. The burdens of endocrine disease such as obesity or type 2 diabetes are believed to arise through a complex interplay between genetics and epigenetic predisposition, environment, nutrition, as well as lifestyle. Therefore, understanding the molecular mechanisms for the onset of endocrine disease will provide new insights for prevention and treatment of these endocrine disorders. There is a growing concern about the dysregulation of micro-RNAs (miRNAs) in endocrine diseases. miRNAs are short noncoding RNA molecules that post-transcriptionally repress the expression of genes by binding to 3′-untranslated regions of the target mRNAs. This chapter aims to provide recent data about the potential involvement of miRNAs in endocrine diseases, such as metabolic syndrome (obesity and type 2 diabetes) or neuroendocrine disorders.

International audience; 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 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.

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.

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.

International audience; 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 TNF alpha-conditioned adipocyte medium (1.5-fold; P < .05). This effect was associated with a reduction in p65 and I kappa B (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) phosphorylation (2-fold compared with TNF alpha; 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 (similar to 2-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.

International audience; 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.

International audience; 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.

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

cope 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.

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.

Introduction et but de l’étude: Au cours de l’obésité, le tissu adipeux est confronté à un ensemble de perturbateurs physiologiques qui vont participer activement au développement de divers désordres physiopathologiques incluant l’inflammation chronique à bas bruit et l’insulino-résistance. De nombreuses études ont montré que les microARNs (miR) pourraient réguler cet état inflammatoire. L’objectif de notre étude a donc été d’identifier les miR régulés au niveau des adipocytes en conditions inflammatoires. Matériel et méthodes: Des miRNA microarrays ont été réalisés sur des adipocytes humains incubés avec différentes doses de TNFα (24 h) afin de déterminer le profil d’expression des différents miR. Nous avons eu recours à des modèles murins (souris aP2-P65, F-p65-KO et Tnfa-/-) et des biopsies de tissu adipeux de 14 patients obèses et 11 normo-pondéraux. Résultats et Analyse statistique: L’analyse des miRNA microarrays a permis de montrer que seul le miR-155 est le plus régulé dans les adipocytes soumis au stress inflammatoire induit par le TNFα. L’implication du TNFα dans l’expression du miR-155 a été confirmée dans le tissu adipeux des souris Tnfa-/-. Cette régulation du miR-155 semble être médiée par la voie de signalisation NF-κB puisque les souris surexprimant p65 présentent une augmentation de l’expression du miR-155 et qu’à l’inverse, les souris F-p65-KO présentent une diminution de l’expression du miR-155. Nous avons montré que miR155 est significativement surexprimé dans le tissu adipeux sous-cutané de patients obèses par rapport aux témoins normo-pondéraux (p

Exercise training is known to stimulate vascular function and remodeling in a shear stress and inflammation dependent manner. Microparticles (MPs) released from vascular cells in response to shear stress, play a role in cell-cell crosstalk through carrying bioactive molecules such as miRNAs. Thus, the aim of our study was to explore whether exercise training impacts vascular wall cells and contributes to vascular function improvement through the modulation of inflammation molecules release. Therefore, we investigated the presence in MPs of 9 inflammation-regulatory miRNAs. A group of sedentary women (n=6, BMI The author hereby declares no conflict of interest

Adipose tissue (AT) homeostasis and growth are dependent on microvasculature. Adipose capillary bed displays a remarkable plasticity, a process called tissue angio-adaptation. In response to metabolic alterations linked to obesity, signaling pathways involved in vascular and microenvironment homeostasis maintenance of AT appear to be affected. We demonstrated that Mdm-2/FoxO1 axis had a key role in muscle angio-adaptive response to exercise affecting pro- (VEGF-A) and anti-angiogenic (TSP-1) factors expression. However, regulation of this process in AT occurring during obesity and/or physical exercise remains unknown. In this context, we studied effects of voluntary exercise in mice fed with a high fat diet (HFD) on the AT vascularization and microenvironment. Trained HFD mice after 7 week-exercise showed a 30% lower body fat mass and 33% reduced epididymal white adipose tissue (eWAT) mass compared to sedentary HFD mice. Histological analysis of eWAT revealed a decreased adipocyte size (-26%) combined with reduced fibrotic area per adipocyte (-45%) in trained HFD vs. sedentary HFD mice. Furthermore, 7 weeks of exercise training of HFD mice stimulated the angiogenesis process in AT with significant increased of capillaries/adipocyte ratio on eWAT (+16%) associated to VEGF-A/TSP-1 expression ratio and Mdm 2 protein expression while FoxO1 protein was decreased. In addition, eWAT inflammatory status evaluated by mRNA analysis indicated that CD11c (M1 macrophage marker), TNFα, IL-6 and leptin (pro-inflammatory cytokines) levels were decreased by 65%, 45% and 55% respectively in comparison to eWAT from sedentary HFD mice. A concomitant increase in Chil3 (M2 macrophage marker) (+84%) and IL-10 (anti-inflammatory cytokine) (+29%) were also observed. In conclusion, our results show that physical exercise acts as a pro-angiogenic stimulus in AT in favor of capillary growth, thru activation of Mdm 2 – FoxO1 and rise of VEGF-A/TSP-1 ratio ultimately promoting an improvement of AT microenvironment by reducing fibrosis, adipocyte hypertrophy and inflammation. The author hereby declares no conflict of interest

Reduced capillary density in adipose tissue is associated with obesity and results in decrease perfusion, decreased oxygen consumption and insulin resistance. Pro- (VEGF-A) and anti-angiogenic (TSP-1) factors expression is central determinant of angiogenesis, with greater VEGF-A/TSP-1 ratio promoting angiogenesis. Since endothelial cells are involved in the pathogenesis of insulin resistance through their role in insulin delivery and adipose tissue angiogenesis, we investigated the role of ECSCR (endothelial cell surface expressed chemotaxis and apoptosis regulator) – Akt axis. In this context, we studied effects of voluntary exercise in mice fed with a high fat diet (HFD) on the AT vascularization. We have demonstrated that 7 weeks-exercise training reduced epididymal and subcutaneous white adipose tissue (eWAT) and (sWAT) mass by 33% and 45% respectively compared to sedentary HFD mice and stimulated capillary growth in AT with a significant increased of capillaries/ adipocyte ratio on eWAT and sWAT (+16% and 28% respectively), associated with a significant VEGF-A/TSP-1 expression ratio increase. Furthermore, while ECSCR protein expression was decreased and associated to a lower ratio of PhosphoAkt/Akt in eWAT and sWAT of HFD mice in comparison to control mice, 7 weeks-exercise training led to a significant increase of ECSCR protein expression associated to the raise of PhosphoAkt/Akt ratio in both eWAT and sWAT. In addition, eWAT and sWAT thermogenic and metabolic activities were stimulated by 7 weeks-exercise training, with increased PGC-1α, Sirt-3 and PPARα in comparison to eWAT and sWAT from sedentary HFD mice. In conclusion, our results indicate that physical exercise acts as a pro-angiogenic stimulus in AT in favor of capillary growth, and that ECSCR – Akt axis as well as VEGF-A/TSP-1 play central role in angioadaptation of AT. The author hereby declares no conflict of interest

Microparticles (MPs) play essential roles in cell-cell crosstalk throw carrying bioactive molecules such as proteins and microRNAs (miRNAs). For this study, the MPs profile was explored in order to understand their implication in endothelial dysfunction in a group of obese (n=69, BMIε30Kg/m2) and normal weight subjects (n=46, BMI

International audience; 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

Stent thrombosis is a serious, although rare, complication of percutaneous coronary intervention (PCI). Some data from randomized trials indicate a higher risk for drug- eluting stents (DES) thrombosis. Furthermore, it has been shown that the most powerful histological predictor of stent thrombosis was endothelial coverage and that reendothelialization was delayed after implantation of first-generation DES compared with baremetal stents (BMS) as from the first month after PCI. We do not have yet simple blood test biomarkers that could reflect the ongoing process of stent reendothelialization. MicroRNAs are small, endogenous, noncoding RNAs, easily detectable in plasma, involved in a variety of cellular processes via suppression of specific target mRNAs and could be such biomarkers. Some of them have been linked to endothelial function and reendothelialization in animal or in vitro studies. We hypothesized that the expression of certain microRNAs was informative of stent endothelialization. We therefore sought beforehand to determine wether stent type and stent length could influence the expression of candidate microRNAs in human peripheral blood. Between July 2008 and December 2013, all patients who underwent coronary angioplasty in our centre were asked to attend a systematic consultation one month after revascularization for blood sampling. Sixty patients with a single-vessel disease meeting over twenty clinical, biological, echocardiographic and angiographic criteria were selected: 30 with a BMS and 30 with a DES, with a balanced ratio of short (≤15mm) and long (>15mm) stents in each group. Twenty eight microRNAs were chosen based on a review of literature. Their expression was measured using qRT-PCR in plasma samples collected at one month. Levels were normalized to cel-miR-39 and compared between the two groups of patients. The results are currently under analysis (table next page).

International audience; Environmental enteric dysfunction (EED) is an inflammatory syndrome postulated to contribute to stunted child growth and to be associated with intestinal dysbiosis and nutrient malabsorption. However, the small intestinal contributions to EED remain poorly understood. This study aimed to assess changes in the proximal and distal intestinal microbiota in the context of stunting and EED and to test for a causal role of these bacterial isolates in the underlying pathophysiology. We performed a cross-sectional study in two African countries recruiting roughly 1,000 children aged 2 to 5 years and assessed the microbiota in the stomach, duodenum, and feces. Upper gastrointestinal samples were obtained from stunted children and stratified according to stunting severity. Fecal samples were collected. We then investigated the role of clinical isolates in EED pathophysiology using tissue culture and animal models. We find that small intestinal bacterial overgrowth (SIBO) is extremely common (>80%) in stunted children. SIBO is frequently characterized by an overgrowth of oral bacteria, leading to increased permeability and inflammation and to replacement of classical small intestinal strains. These duodenal bacterial isolates decrease lipid absorption in both cultured enterocytes and mice, providing a mechanism by which they may exacerbate EED and stunting. Further, we find a specific fecal signature associated with the EED markers fecal calprotectin and alpha-antitrypsin. Our study shows a causal implication of ectopic colonization of oral bacterial isolated from the small intestine in nutrient malabsorption and gut leakiness in vitro. These findings have important therapeutic implications for modulating the microbiota through microbiota-targeted interventions.

International audience; Environmental enteric dysfunction (EED) is an elusive, inflammatory syndrome of the small intestine thought to be associated with enterocyte loss and gut leakiness and lead to stunted child growth. To date, the gold standard for diagnosis is small intestine biopsy followed by histology. Several putative biomarkers for EED have been proposed and are widely used in the field. Here, we assessed in a cross-sectional study of children aged 2–5 years for a large set of biomarkers including markers of protein exudation (duodenal and fecal alpha-1-antitrypsin (AAT)), inflammation (duodenal and fecal calprotectin, duodenal, fecal and blood immunoglobulins, blood cytokines, C-reactive protein (CRP)), gut permeability (endocab, lactulose-mannitol ratio), enterocyte mass (citrulline) and general nutritional status (branched-chain amino acids (BCAA), insulin-like growth factor) in a group of 804 children in two Sub-Saharan countries. We correlated these markers with each other and with anemia in stunted and non-stunted children. AAT and calprotectin, CRP and citrulline and citrulline and BCAA correlated with each other. Furthermore, BCAA, citrulline, ferritin, fecal calprotectin and CRP levels were correlated with hemoglobin levels. Our results show that while several of the biomarkers are associated with anemia, there is little correlation between the different biomarkers. Better biomarkers and a better definition of EED are thus urgently needed.

International audience; Environmental enteric dysfunction (EED) is an inflammatory syndrome postulated to contribute to stunted child growth and to be associated with intestinal dysbiosis and nutrient malabsorption. However, the small intestinal contributions to EED remain poorly understood. This study aimed to assess changes in the proximal and distal intestinal microbiota in the context of stunting and EED and to test for a causal role of these bacterial isolates in the underlying pathophysiology. We performed a cross-sectional study in two African countries recruiting roughly 1,000 children aged 2 to 5 years and assessed the microbiota in the stomach, duodenum, and feces. Upper gastrointestinal samples were obtained from stunted children and stratified according to stunting severity. Fecal samples were collected. We then investigated the role of clinical isolates in EED pathophysiology using tissue culture and animal models. We find that small intestinal bacterial overgrowth (SIBO) is extremely common (>80%) in stunted children. SIBO is frequently characterized by an overgrowth of oral bacteria, leading to increased permeability and inflammation and to replacement of classical small intestinal strains. These duodenal bacterial isolates decrease lipid absorption in both cultured enterocytes and mice, providing a mechanism by which they may exacerbate EED and stunting. Further, we find a specific fecal signature associated with the EED markers fecal calprotectin and alpha-antitrypsin. Our study shows a causal implication of ectopic colonization of oral bacterial isolated from the small intestine in nutrient malabsorption and gut leakiness in vitro. These findings have important therapeutic implications for modulating the microbiota through microbiota-targeted interventions.