Virginie Bourlier

Unité Inserm U1077, Caen, Lower Normandy, France

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Publications (23)117.82 Total impact

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    ABSTRACT: Introduction La régulation des cellules T dans le tissu adipeux constitue un lien important entre l’inflammation et l’insulino-résistance. Nous avons recherché les cellules présentatrices d’antigènes dans le tissu adipeux des souris et patients obèses en fonction de l’insulino-résistance. Patients et méthodes Les cellules dendritiques ont été étudiées dans le tissu adipeux de souris minces, obèses (HFD), Rag1–/–, de 20 patients avec des IMC allant de 19,5 à 38 kg/m2, ainsi que des patients obèses morbides sans (n = 10) ou avec un diabète de type 2 (n = 110) par des approches de cytométrie en flux et PCR quantitative Résultats Chez la souris mince, la présence des CDs résidantes (CD11chighF4/80neg) est détectée dans le tissu adipeux epididymaire. Chez des souris déficientes en cellules T, le transfert adoptif de cellules T naïve spécifique à l’ovalbumine induit majoritairement une réponse de type Th1 en réponse à l’ovalbumine dans le tissu adipeux. Dans les souris et patients obèses, les CDs (CD11c+CD1c+ chez l’homme et CD11chighF4/80lowCX3CR1pos chez la souris) sont majoritairement accumulées dans le tissu adipeux. Les CDs CD11chighF4/80low isolées chez les souris obèses induisent, ex-vivo, la polarisation des cellules T naïves en cellules Th17. Dans une cohorte de 20 patients, le nombre de cellules CD1c+CD11c+ par g de tissu adipeux sous-cutanés est corrélé à IMC (rs = 10,4947; P < 0,05). Chez des patients obèses morbides, l’expression génique de CD1c dans la tissu adipeux sous-cutané est plus importante chez les patients diabétiques versus les patients obèses, et est corrélé à HOMA-IR (rs = 10,560; P = 10,013). Conclusion Nous montrons, pour la première fois, la présence et l’accumulation des CDs dans le tissu adipeux en fonction de l’obésité et de l’insulino-résistance chez la souris et les patients. Ces cellules dendritiques sont fonctionnelles et pourraient favoriser la polarisation des cellules T en Th1 et Th17 dans le tissu adipeux inflammé.
    Diabetes & Metabolism; 05/2014
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    ABSTRACT: j.celrep.2014.03.062 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). SUMMARY Adipose tissue fibrosis development blocks adipo-cyte hypertrophy and favors ectopic lipid accumula-tion. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in hu-mans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte meta-bolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a func-tional Toll-like receptor 4 on adipose tissue hemato-poietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, pro-motes adipose tissue fibrosis. Ex vivo, lipopolysac-charide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFb1. Together, these results indicate that obesity and en-dotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resis-tance, through immune cell Toll-like receptor 4. INTRODUCTION
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    ABSTRACT: Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFβ1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4.
    Cell Reports 04/2014; · 7.21 Impact Factor
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    ABSTRACT: Introduction Les triglycérides intramusculaires constituent une source d’énergie importante pour le muscle squelettique notamment au cours d’un exercice physique. Des travaux récents suggèrent que l’ATGL (adipose triglyceride lipase) joue un rôle clé dans ce processus. Cependant, peu de données sont actuellement disponibles sur le contrôle de son activité. L’objectif de ce travail était d’étudier le rôle de la protéine G0/G1 Switch Gene 2 (G0S2), récemment décrite comme inhibitrice de l’ATGL dans le tissu adipeux, dans la régulation de la lipolyse et du métabolisme oxydatif musculaire. Matériels et méthodes L’expression de G0S2 a été diminuée, à l’aide de lentivirus contenant des shRNA, dans des cultures primaires de cellules musculaires squelettiques humaines (i.e. myotubes) issues de biopsies de rectus abdominis obtenues chez des volontaires sains. L’activité de l’ATGL, le contenu en triglycérides, la mobilisation et l’oxydation des acides gras, l’oxydation du glucose et la synthèse de glycogène ont été évalués à l’aide de substrats radiomarqués. Les approches métaboliques ont été complétées par des études d’immunofluorescence des mitochondries et d’expression de gènes clés par RT-qPCR. Résultats Nos résultats montrent que G0S2 est exprimé dans les myotubes et qu’il inhibe l’activité de l’ATGL. Son invalidation induit une diminution du pool de triglycérides et une augmentation de la mobilisation et de l’oxydation des acides gras. L’oxydation du glucose et la synthèse de glycogène sont diminuées. L’augmentation du flux d’acides gras s’accompagne d’une hausse de la masse et du potentiel de membrane des mitochondries. Ces effets seraient potentiellement médiés par l’induction de gènes cibles du Peroxysome Proliferator Activated Receptor δ (PPARδ). Conclusion Ces résultats indiquent que G0S2 joue un rôle majeur dans la régulation de la lipolyse et du métabolisme oxydatif musculaire, en modulant le flux d’acides gras et l’expression de gènes cibles de PPARδ.
    Diabetes & Metabolism 03/2014; 40:A3–A4. · 2.39 Impact Factor
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    ABSTRACT: The aim of the present study was to investigate the influence of substrate availability on fuel selection during exercise. Eight endurance-trained male cyclists performed 90-min exercise at 70 % of their maximal oxygen uptake in a cross-over design, either in rested condition (CON) or the day after 2-h exercise practised at 70 % of maximal oxygen uptake (EX). Subjects were given a sucrose load (0.75 g kg(-1) body weight) 45 min after the beginning of the 90-min exercise test. Lipolysis was measured in subcutaneous abdominal adipose tissue (SCAT) by microdialysis and substrate oxidation by indirect calorimetry. Lipid oxidation increased during exercise and tended to decrease during sucrose ingestion in both conditions. Lipid oxidation was higher during the whole experimental period in the EX group (p = 0.004). Interestingly, fuel selection, assessed by the change in respiratory exchange ratio (RER), was increased in the EX session (p = 0.002). This was paralleled by a higher rate of SCAT lipolysis reflected by dialysate glycerol, plasma glycerol, and fatty acids (FA) levels (p < 0.001). Of note, we observed a significant relationship between whole-body fat oxidation and dialysate glycerol in both sessions (r (2) = 0.33, p = 0.02). In conclusion, this study highlights the limiting role of lipolysis and plasma FA availability to whole-body fat oxidation during exercise in endurance-trained subjects. This study shows that adipose tissue lipolysis is a determinant of fuel selection during exercise in healthy subjects.
    Journal of physiology and biochemistry 12/2013; · 1.65 Impact Factor
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    ABSTRACT: Context:Skeletal muscle lipase and intramyocellular triglyceride (IMTG) play a role in obesity-related metabolic disorders.Objectives:The aim of the present study was to investigate the impact of 8 weeks of endurance exercise training on IMTG content and lipolytic proteins in obese male subjects.Design and Volunteers:Ten obese subjects completed an 8-week supervised endurance exercise training intervention in which vastus lateralis muscle biopsy samples were collected before and after training.Main Outcome Measures:Clinical characteristics and ex vivo substrate oxidation rates were measured pre- and posttraining. Skeletal muscle lipid content and lipolytic protein expression were also investigated.Results:Our data show that exercise training reduced IMTG content by 42% (P < .01) and increased skeletal muscle oxidative capacity, whereas no change in total diacylglycerol content and glucose oxidation was found. Exercise training up-regulated adipose triglyceride lipase, perilipin (PLIN) 3 protein, and PLIN5 protein contents in skeletal muscle despite no change in mRNA levels. Training also increased hormone sensitive-lipase Ser660 phosphorylation. No significant changes in comparative gene identification 58, G0/G1 switch gene 2, and PLIN2 protein and mRNA levels were observed in response to training. Interestingly, we noted a strong relationship between skeletal muscle comparative gene identification 58 and mitochondrial respiratory chain complex I protein contents at baseline (r = 0.87, P < .0001).Conclusions:Endurance exercise training coordinately up-regulates fat oxidative capacity and lipolytic protein expression in skeletal muscle of obese subjects. This physiological adaptation probably favors fat oxidation and may alleviate the lipotoxic lipid pressure in skeletal muscle. Enhancement of IMTG turnover may be required for the beneficial metabolic effects of exercise in obesity.
    The Journal of Clinical Endocrinology and Metabolism 10/2013; · 6.31 Impact Factor
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    ABSTRACT: Context:It was suggested that human cultured primary myotubes retain the metabolic characteristics of their donor in vitro.Objectives:The aim of the present study was to investigate whether the metabolic responses to endurance training are also conserved in culture.Design and Volunteers:Middle-aged obese subjects completed an 8-week supervised aerobic exercise training program in which vastus lateralis muscle biopsies were collected before and after training.Main Outcome Measures:Anthropometric and blood parameters, as well as aerobic capacity, were assessed before and after training. Muscle biopsies were either used for Western blot analysis or digested to harvest myogenic progenitors that were differentiated into myotubes. Glucose oxidation, palmitate oxidation, and glycogen synthesis assays were performed on myotubes before and after training. Gene expression was assessed by real-time quantitative PCR.Results:Our data indicate that in parallel of in vivo improvement of whole-body aerobic capacity and glucose metabolism, biopsy-derived primary myotubes showed similar patterns in vitro. Indeed, glucose oxidation, glycogen synthesis, and inhibition of palmitate oxidation by glucose were enhanced in myotubes after training. This was associated with consistent changes in the expression of metabolism-linked genes such as GLUT1, PDK4, and PDHA1. Interestingly, no difference in myogenic differentiation capacity was observed before and after training.Conclusion:Aerobic exercise training is associated with metabolic adaptations in vivo that are preserved in human cultured primary myotubes. It can be hypothesized that skeletal muscle microenvironmental changes induced by endurance training lead to metabolic imprinting on myogenic progenitor cells.
    The Journal of Clinical Endocrinology and Metabolism 07/2013; · 6.31 Impact Factor
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    ABSTRACT: Elevated expression/activity of adipose triglyceride lipase (ATGL) and/or reduced activity of hormone-sensitive lipase (HSL) in skeletal muscle are causally linked to insulin resistance in vitro. We investigated here the effect of high-fat feeding on skeletal muscle lipolytic proteins, lipotoxicity, and insulin signaling in vivo. Five-week-old C3H mice were fed normal chow diet (NCD) or 45% kcal high-fat diet (HFD) for 4 weeks. Wild-type and HSL knockout mice fed NCD were also studied. Whole-body and muscle insulin sensitivity, as well as lipolytic protein expression, lipid levels, and insulin signaling in skeletal muscle, were measured. HFD induced whole-body insulin resistance and glucose intolerance and reduced skeletal muscle glucose uptake compared with NCD. HFD increased skeletal muscle total diacylglycerol (DAG) content, protein kinase Cθ and protein kinase Cε membrane translocation, and impaired insulin signaling as reflected by a robust increase of basal Ser1101 insulin receptor substrate 1 phosphorylation (2.8-fold, P < .05) and a decrease of insulin-stimulated v-Akt murine thymoma viral oncogene homolog Ser473 (-37%, P < .05) and AS160 Thr642 (-47%, P <.01) phosphorylation. We next showed that HFD strongly reduced HSL phosphorylation at Ser660. HFD significantly up-regulated the muscle protein content of the ATGL coactivator comparative gene identification 58 and triacylglycerol hydrolase activity, despite a lower ATGL protein content. We further show a defective skeletal muscle insulin signaling and DAG accumulation in HSL knockout compared with wild-type mice. Together, these data suggest a pathophysiological link between altered skeletal muscle lipase expression and DAG-mediated insulin resistance in mice.
    Endocrinology 03/2013; · 4.72 Impact Factor
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    ABSTRACT: Cardiac natriuretic peptides (NP) are major activators of human fat cell lipolysis and have recently been shown to control brown fat thermogenesis. Here, we investigated the physiological role of NP on the oxidative metabolism of human skeletal muscle. NP receptor type A (NPRA) gene expression was positively correlated to mRNA levels of PPARγ coactivator-1α (PGC1A) and several oxidative phosphorylation (OXPHOS) genes in human skeletal muscle. Further, the expression of NPRA, PGC1A, and OXPHOS genes was coordinately upregulated in response to aerobic exercise training in human skeletal muscle. In human myotubes, NP induced PGC-1α and mitochondrial OXPHOS gene expression in a cyclic GMP-dependent manner. NP treatment increased OXPHOS protein expression, fat oxidation, and maximal respiration independent of substantial changes in mitochondrial proliferation and mass. Treatment of myotubes with NP recapitulated the effect of exercise training on muscle fat oxidative capacity in vivo. Collectively, these data show that activation of NP signaling in human skeletal muscle enhances mitochondrial oxidative metabolism and fat oxidation. We propose that NP could contribute to exercise training-induced improvement in skeletal muscle fat oxidative capacity in humans.
    The Journal of clinical investigation 11/2012; · 15.39 Impact Factor
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    ABSTRACT: Leukotrienes (LTs) are potent proinflammatory mediators, and many important aspects of innate and adaptive immune responses are regulated by LTs. Key members of the LT synthesis pathway are overexpressed in adipose tissue (AT) during obesity, resulting in increased LT levels in this tissue. We observed that several mouse adipocyte cell lines and primary adipocytes from mice and humans both can secrete large amounts of LTs. Furthermore, this production increases with a high-fat diet (HFD) and positively correlates with adipocyte size. LTs produced by adipocytes play an important role in attracting macrophages and T cells in in vitro chemotaxis assays. Mice that are deficient for the enzyme 5-lipoxygenase (5-LO), and therefore lack LTs, exhibit a decrease in HFD-induced AT macrophage and T-cell infiltration and are partially protected from HFD-induced insulin resistance. Similarly, treatment of HFD-fed wild-type mice with the 5-LO inhibitor Zileuton also results in a reduction of AT macrophages and T cells, accompanied by a decrease in insulin resistance. Together, these findings suggest that LTs represent a novel target in the prevention or treatment of obesity-associated inflammation and insulin resistance.
    Diabetes 06/2012; 61(9):2311-9. · 7.90 Impact Factor
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    ABSTRACT: T-cell regulation in adipose tissue provides a link between inflammation and insulin resistance. Because of alterations in adipose tissue T-cell composition in obesity, we aimed to identify the antigen-presenting cells in adipose tissue of obese mice and patients with insulin resistance. Dendritic cells (DCs) and T cells were studied in mice and in two cohorts of obese patients. In lean mice, only CD11c(+) DCs were detected in adipose tissue. Adoptive transfer of naive CD4(+) T cells in Rag1(-/-) mice led to a predominant Th1 response in adipose tissue. In contrast, during obesity DCs (human CD11c(+)CD1c(+) and mouse CD11c(high)F4/80(low)) accumulated in adipose tissue. CD11c(high)F4/80(low) DCs from obese mice induced Th17 differentiation. In patients, the presence of CD11c(+)CD1c(+) DCs correlated with the BMI and with an elevation in Th17 cells. In addition, these DCs led to ex vivo Th17 differentiation. CD1c gene expression further correlated with homeostatic model assessment-insulin resistance in the subcutaneous adipose tissue of obese patients. We show for the first time the presence and accumulation of specific DCs in adipose tissue in mouse and human obesity. These DCs were functional and could be important regulators of adipose tissue inflammation by regulating the switch toward Th17 cell responses in obesity-associated insulin resistance.
    Diabetes 05/2012; 61(9):2238-47. · 7.90 Impact Factor
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    ABSTRACT: We investigated here the specific role of CGI-58 in the regulation of energy metabolism in skeletal muscle. We first examined CGI-58 protein expression in various muscle types in mice, and next modulated CGI-58 expression during overexpression and knockdown studies in human primary myotubes and evaluated the consequences on oxidative metabolism. We observed a preferential expression of CGI-58 in oxidative muscles in mice consistent with triacylglycerol hydrolase activity. We next showed by pulse-chase that CGI-58 overexpression increased by more than 2-fold the rate of triacylglycerol (TAG) hydrolysis, as well as TAG-derived fatty acid (FA) release and oxidation. Oppositely, CGI-58 silencing reduced TAG hydrolysis and TAG-derived FA release and oxidation (-77%, P < 0.001), whereas it increased glucose oxidation and glycogen synthesis. Interestingly, modulations of CGI-58 expression and FA release are reflected by changes in pyruvate dehydrogenase kinase 4 gene expression. This regulation involves the activation of the peroxisome proliferator activating receptor-δ (PPARδ) by lipolysis products. Altogether, these data reveal that CGI-58 plays a limiting role in the control of oxidative metabolism by modulating FA availability and the expression of PPARδ-target genes, and highlight an important metabolic function of CGI-58 in skeletal muscle.
    The Journal of Lipid Research 02/2012; 53(5):839-48. · 4.39 Impact Factor
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    ABSTRACT: The present study was undertaken to characterize the remodeling phenotype of human adipose tissue (AT) macrophages (ATM) and to analyze their paracrine effects on AT progenitor cells. The phenotype of ATM, immunoselected from subcutaneous (Sc) AT originating from subjects with wide range of body mass index and from paired biopsies of Sc and omental (Om) AT from obese subjects, was studied by gene expression analysis in the native and activated states. The paracrine effects of ScATM on the phenotype of human ScAT progenitor cells (CD34(+)CD31(-)) were investigated. Two main ATM phenotypes were distinguished based on gene expression profiles. For ScAT-derived ATM, obesity and adipocyte-derived factors favored a pro-fibrotic/remodeling phenotype whereas the OmAT location and hypoxic culture conditions favored a pro-angiogenic phenotype. Treatment of native human ScAT progenitor cells with ScATM-conditioned media induced the appearance of myofibroblast-like cells as shown by expression of both α-SMA and the transcription factor SNAIL, an effect mimicked by TGFβ1 and activinA. Immunohistochemical analyses showed the presence of double positive α-SMA and CD34 cells in the stroma of human ScAT. Moreover, the mRNA levels of SNAIL and SLUG in ScAT progenitor cells were higher in obese compared with lean subjects. Human ATM exhibit distinct pro-angiogenic and matrix remodeling/fibrotic phenotypes according to the adiposity and the location of AT, that may be related to AT microenvironment including hypoxia and adipokines. Moreover, human ScAT progenitor cells have been identified as target cells for ScATM-derived TGFβ and as a potential source of fibrosis through their induction of myofibroblast-like cells.
    PLoS ONE 01/2012; 7(2):e31274. · 3.53 Impact Factor
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    ABSTRACT: Our goal was to identify a set of human adipose tissue macrophage (ATM)-specific markers and investigate whether their gene expression in subcutaneous adipose tissue (SAT) as well as in visceral adipose tissue (VAT) is related to obesity and to the occurrence of the metabolic syndrome. ATM-specific markers were identified by DNA microarray analysis of adipose tissue cell types isolated from SAT of lean and obese individuals. We then analysed gene expression of these markers by reverse transcription quantitative PCR in paired samples of SAT and VAT from 53 women stratified into four groups (lean, overweight, obese and obese with the metabolic syndrome). Anthropometric measurements, euglycaemic-hyperinsulinaemic clamp, blood analysis and computed tomography scans were performed. A panel of 24 genes was selected as ATM-specific markers based on overexpression in ATM compared with other adipose tissue cell types. In SAT and VAT, gene expression of ATM markers was lowest in lean and highest in the metabolic syndrome group. mRNA levels in the two fat depots were negatively correlated with glucose disposal rate and positively associated with indices of adiposity and the metabolic syndrome. In humans, expression of ATM-specific genes increases with the degree of adiposity and correlates with markers of insulin resistance and the metabolic syndrome to a similar degree in SAT and in VAT.
    Diabetologia 01/2011; 54(4):876-87. · 6.49 Impact Factor
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    ABSTRACT: Growth of white adipose tissue takes place in normal development and in obesity. A pool of adipose progenitors is responsible for the formation of new adipocytes and for the potential of this tissue to expand in response to chronic energy overload. However, factors controlling self-renewal of human adipose progenitors are largely unknown. We investigated the expression profile and the role of activin A in this process. Expression of INHBA/activin A was investigated in three types of human adipose progenitors. We then analyzed at the molecular level the function of activin A during human adipogenesis. We finally investigated the status of activin A in adipose tissues of lean and obese subjects and analyzed macrophage-induced regulation of its expression. INHBA/activin A is expressed by adipose progenitors from various fat depots, and its expression dramatically decreases as progenitors differentiate into adipocytes. Activin A regulates the number of undifferentiated progenitors. Sustained activation or inhibition of the activin A pathway impairs or promotes, respectively, adipocyte differentiation via the C/EBPβ-LAP and Smad2 pathway in an autocrine/paracrine manner. Activin A is expressed at higher levels in adipose tissue of obese patients compared with the expression levels in lean subjects. Indeed, activin A levels in adipose progenitors are dramatically increased by factors secreted by macrophages derived from obese adipose tissue. Altogether, our data show that activin A plays a significant role in human adipogenesis. We propose a model in which macrophages that are located in adipose tissue regulate adipose progenitor self-renewal through activin A.
    Diabetes 10/2010; 59(10):2513-21. · 7.90 Impact Factor
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    ABSTRACT: Adipose tissue (AT) plays a major role in the low-grade inflammatory state associated with obesity. The aim of the present study was to characterize the human AT lymphocytes (ATLs) and to analyze their interactions with adipocytes. Human ATL subsets were characterized by flow cytometry in subcutaneous ATs from 92 individuals with body mass index (BMI) ranging from 19 to 43 kg/m(2) and in paired biopsies of subcutaneous and visceral AT from 45 class II/III obese patients. CD3(+) ATLs were composed of effector and memory CD4(+) helper and CD8(+) cytotoxic T cells. The number of ATLs correlated positively with BMI and was higher in visceral than subcutaneous AT. Mature adipocytes stimulated the migration of ATLs and released the chemokine CCL20, the receptor of which (CCR6) was expressed in ATLs. The expression of adipocyte CCL20 was positively correlated with BMI and increased in visceral compared to subcutaneous adipocytes. ATLs expressed inflammatory markers and released interferon gamma (IFN gamma). Progenitor and adipocyte treatment with ATL-conditioned media reduced the insulin-mediated upregulation of lipogenic enzymes, an effect involving IFN gamma. Therefore, crosstalk occurs between adipocytes and lymphocytes within human AT involving T cell chemoattraction by adipocytes and modulation of lipogenesis by ATLs.
    Arteriosclerosis Thrombosis and Vascular Biology 08/2009; 29(10):1608-14. · 6.34 Impact Factor
  • V. Bourlier, A. Bouloumie
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    ABSTRACT: Obesity is associated with systemic chronic low-grade inflammation, a major contributor to the aetiology of insulin resistance (IR). An inflammatory response in the presence of obesity appears to be triggered by, and to reside predominantly in, adipose tissue (AT). The discovery that the AT in obese mice and humans is infiltrated with macrophages has provided a major advance in our understanding of how obesity propagates inflammation. Interestingly, AT-infiltrating macrophages exhibit a proinflammatory phenotype (classical activation) whereas macrophages residing in AT have a reparative phenotype (alternative activation). In this review, the processes involved in monocyte/macrophage recruitment into the AT, and the events underlying the activation of infiltrating and/or resident AT macrophages (ATM) are described. Also, the localized roles of ATM on AT growth, metabolism and remodelling, as well as their systemic effects in promoting IR, are revealed. Finally, the new therapeutic targets that have recently emerged, and which have the potential to modulate the recruitment and/or activation of ATM, are discussed.RésuméDans cette revue, sont discutés les mécanismes par lesquels l’accumulation de macrophages au sein du tissu adipeux essentiellement fait le lien entre obésité et insulinorésistance. En effet, l’inflammation systémique de bas bruit associée au développement excessif de la masse grasse semble être en grande partie responsable de la perte de sensibilité tissulaire à l’insuline. Or, le tissu adipeux est le lieu principal des processus inflammatoires et il a été rapporté tant chez les rongeurs que chez l’homme une augmentation du contenu en macrophages avec l’obésité. Contrairement aux macrophages résidents, ces macrophages nouvellement recrutés ont un phénotype pro-inflammatoire qui pouvait expliquer la propagation de l’inflammation associée à l’obésité. Les phénomènes potentiellement impliqués dans le recrutement et l’activation des macrophages du tissu adipeux sont exposés. Pour finir, l’impact local de l’accumulation des macrophages du tissu adipeux sur le développement, le métabolisme et le remodelage du tissu adipeux ainsi que les répercussions systémiques engendrées par la présence de macrophages au sein du tissu adipeux sont abordés et rattachés à la mise en place de l’insulinorésistance au niveau du tissu adipeux lui-même, mais également au niveau des muscles squelettiques et du foie. L’émergence de nouvelles cibles thérapeutiques qui affectent le recrutement et/ou l’activation des macrophages du tissu adipeux est discutée dans les perspectives.
    Diabetes & Metabolism. 01/2009;
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    ABSTRACT: Adipocyte formation in human adult adipose tissue (hAT) originates from resident progenitor cell differentiation in the stroma vascular fraction of the AT. The processes involved in the self-renewal of this cell population remain to be defined. The objective was to study in situ and in vitro hAT progenitor cell (defined as CD34(+)/CD31(-) cells) proliferation. In situ progenitor cell proliferation was assessed by immunohistochemistry and flow cytometry analyses on hAT from lean to obese subjects using the proliferation marker Ki-67. The effects of adipokines, hypoxia, and conditioned media (CM) from adipocytes, capillary endothelial cells, and macrophages isolated by an immunoselection approach were studied on hAT progenitor cell growth. Cell death in hAT was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein end labeling method. Ki-67-positive staining was observed in AT progenitor cells. Fat mass enlargement in obese patients was associated with an increased Ki-67(+) progenitor cell population together with a new fraction of small adipocytes and increased cell death. HIF-1alpha mRNA expression in freshly harvested progenitor cells was positively correlated with body mass index. Adipocyte- and capillary endothelial cell-CM, hypoxia, leptin, IL-6, lysophosphatidic acid, and vascular endothelial growth factor, all increased hAT progenitor cell proliferation in vitro. Macrophage-CM had an antiproliferative effect that was suppressed by an antioxidant. The fraction of proliferative progenitor cells in adult hAT is modulated by the degree of adiposity. Changes in the progenitor cell microenvironment involving adipokines, hypoxia, and oxidative stress might play a key role in the control of the self-renewal of the local pool of AT progenitor cells.
    Journal of Clinical Endocrinology &amp Metabolism 09/2008; 93(10):4098-106. · 6.43 Impact Factor
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    ABSTRACT: Adipose tissue macrophages (ATMs) have become a focus of attention recently because they have been shown to accumulate with an increase in fat mass and to be involved in the genesis of insulin resistance in obese mice. However, the phenotype and functions of human ATMs are still to be defined. The present study, performed on human subcutaneous AT, showed that ATMs from lean to overweight individuals are composed of distinct macrophage subsets based on the expression of several cell surface markers: CD45, CD14, CD31, CD44, HLA-DR, CD206, and CD16, as assessed by flow cytometry. ATMs isolated by an immunoselection protocol showed a mixed expression of proinflammatory (tumor necrosis factor-alpha, interleukin-6 [IL-6], IL-23, monocyte chemoattractant protein-1, IL-8, cyclooxygenase-2) and antiinflammatory (IL-10, transforming growth factor-beta, alternative macrophage activation-associated cc chemokine-1, cyclooxygenase-1) factors. Fat mass enlargement is associated with accumulation of the CD206+/CD16- macrophage subset that exhibits an M2 remodeling phenotype characterized by decreased expression of proinflammatory IL-8 and cyclooxygenase-2 and increased expression of lymphatic vessel endothelial hyaluronan receptor-1. ATMs specifically produced and released matrix metalloproteinase-9 compared with adipocytes and capillary endothelial cells, and secretion of matrix metalloproteinase-9 from human AT in vivo, assessed by arteriovenous difference measurement, was correlated with body mass index. Finally, ATMs exerted a marked proangiogenic effect on AT-derived endothelial and progenitor cells. The present results showed that the ATMs that accumulate with fat mass development exhibit a particular M2 remodeling phenotype. ATMs may be active players in the process of AT development through the extension of the capillary network and in the genesis of obesity-associated cardiovascular pathologies.
    Circulation 03/2008; 117(6):806-15. · 15.20 Impact Factor
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    ABSTRACT: In a previous publication, we reported that human immunodeficiency virus (HIV) protease inhibitors (PIs) inhibited the differentiation of human preadipocytes in primary culture, reducing the expression and secretion of matrix metalloproteinase 9 (MMP-9). The present work was performed to clarify this mechanism. Interestingly, HIV-PIs have been reported to be inhibitors of the proteasome complex, which is known to regulate nuclear factor (NF)-kappaB activation and transcription of its target genes, among them MMP-9. We thus investigated the potential involvement of the proteasome in the antiadipogenic effects of HIV-PIs. The effect of four HIV-PIs was tested on preadipocyte proteasomal activity, and chronic treatment with the specific proteasome inhibitor lactacystin was performed to evaluate alterations of adipogenesis and MMP-9 expression/secretion. Finally, modifications of the NF-kappaB pathway induced by either HIV-PIs or lactacystin were studied. We demonstrated that preadipocyte proteasomal activity was decreased by several HIV-PIs and that chronic treatment with lactacystin mimicked the effects of HIV-PIs by reducing adipogenesis and MMP-9 expression/secretion. Furthermore, we observed an intracellular accumulation of the NF-kappaB inhibitor, IkappaBbeta, with chronic treatment with HIV-PIs or lactacystin as well as a decrease in MMP-9 expression induced by acute tumor necrosis factor-alpha stimulation. These results indicate that inhibition of the proteasome by specific (lactacystin) or nonspecific (HIV-PIs) inhibitors leads to a reduction of human adipogenesis, and they therefore implicate deregulation of the NF-kappaB pathway and the related decrease of the key adipogenic factor, MMP-9. This study adds significantly to recent reports that have linked HIV-PI-related lipodystrophic syndrome with altered proteasome function, endoplasmic reticulum stress, and metabolic disorders.
    Journal of Pharmacology and Experimental Therapeutics 02/2007; 320(1):291-9. · 3.89 Impact Factor

Publication Stats

448 Citations
117.82 Total Impact Points

Institutions

  • 2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2007–2012
    • Paul Sabatier University - Toulouse III
      • Institut des Maladies Métaboliques et Cardiovasculaires de Toulouse - UMRS 1048 - I2MC
      Toulouse, Midi-Pyrenees, France
  • 2011
    • University of Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2005–2009
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France