Philippe Valet

Paul Sabatier University - Toulouse III, Tolosa de Llenguadoc, Midi-Pyrénées, France

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Publications (250)1004.18 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Over the two past decades, mutations of the PTPN11 gene, encoding the ubiquitous protein tyrosine phosphatase SHP2 (SH2 domain-containing tyrosine phosphatase 2), have been identified as the causal factor of several developmental diseases (Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML), and metachondromatosis), and malignancies (juvenile myelomonocytic leukaemia). SHP2 plays essential physiological functions in organism development and homeostasis maintenance by regulating fundamental intracellular signaling pathways in response to a wide range of growth factors and hormones, notably the pleiotropic Ras/Mitogen-Activated Protein Kinase (MAPK) and the Phosphoinositide-3 Kinase (PI3K)/AKT cascades. Analysis of the biochemical impacts of PTPN11 mutations first identified both loss-of-function and gain-of-function mutations, as well as more subtle defects, highlighting the major pathophysiological consequences of SHP2 dysregulation. Then, functional genetic studies provided insights into the molecular dysregulations that link SHP2 mutants to the development of specific traits of the diseases, paving the way for the design of specific therapies for affected patients. In this review, we first provide an overview of SHP2's structure and regulation, then describe its molecular roles, notably its functions in modulating the Ras/MAPK and PI3K/AKT signalling pathways, and its physiological roles in organism development and homeostasis. In the second part, we describe the different PTPN11 mutation-associated pathologies and their clinical manifestations, with particular focus on the biochemical and signalling outcomes of NS and NS-ML-associated mutations, and on the recent advances regarding the pathophysiology of these diseases. Copyright © 2015. Published by Elsevier Masson SAS.
    European journal of medical genetics 09/2015; DOI:10.1016/j.ejmg.2015.08.005 · 1.47 Impact Factor
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    ABSTRACT: Sterol response element binding protein (SREBP) is a key transcription factor in insulin and glucose metabolism. We previously demonstrated that elevated levels of membrane sphingomyelin (SM) were related to peroxisome proliferator-activated receptor-γ (PPARγ), which is a known target gene of SREBP-1 in adipocytes. However, the role of SM in SREBP expression in adipocytes remains unknown. In human abdominal adipose tissue from obese women with various concentrations of fasting plasma insulin, SREBP-1 proteins decreased in parallel with increases in membrane SM levels. An inverse correlation was found between the membrane SM content and the levels of SREBP-1c/ERK/Ras/PPARγ/CREB proteins. For the first time, we demonstrate the effects of SM and its signaling pathway in 3T3-F442A adipocytes. These cells were enriched or unenriched with SM in a range of concentrations similar to those observed in obese subjects by adding exogenous natural SMs (having different acyl chain lengths) or by inhibiting neutral sphingomyelinase. SM accumulated in caveolae of the plasma membrane within 24 h and then in the intracellular space. SM enrichment decreased SREBP-1 through the inhibition of extracellular signal-regulated protein kinase (ERK) but not JNK or p38 mitogen-activated protein kinase (MAPK). Ras/Raf-1/MEK1/2 and KSR proteins, which are upstream mediators of ERK, were down-regulated, whereas SREBP-2/caveolin and cholesterol were up-regulated. In SM-unmodulated adipocytes treated with DL-1-Phenyl-2-Palmitoylamino-3-morpholino-1-propanol (PPMP), where the ceramide level increased, the expression levels of SREBPs and ERK were modulated in an opposite direction relative to the SM-enriched cells. SM inhibited the insulin-induced expression of SREBP-1. Rosiglitazone, which is an anti-diabetic agent and potent activator of PPARγ, reversed the effects of SM on SREBP-1, PPARγ and CREB. Taken together, these findings provide novel insights indicating that excess membrane SM might be critical for regulating SREBPs in adipocytes via a MAPK-dependent pathway.
    PLoS ONE 08/2015; 10(7):e0133181. DOI:10.1371/journal.pone.0133181 · 3.23 Impact Factor
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    ABSTRACT: A high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 07/2015; 22(1):100-12. DOI:10.1016/j.cmet.2015.06.001 · 17.57 Impact Factor
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    ABSTRACT: The G protein-coupled receptor APJ and its cognate ligand, apelin, are widely expressed throughout human body. They are implicated in different key physiological processes such as angiogenesis, cardiovascular functions, fluid homeostasis and energy metabolism regulation. On the other hand, this couple ligand-receptor is also involved in the development and progression of different pathologies including diabetes, obesity, cardiovascular disease and cancer. Recently, a new endogenous peptidic ligand of APJ, named Elabela/Toddler, has been identified and shown to play a crucial role in embryonic development. Whereas nothing is yet known regarding Elabela/Toddler functions in adulthood, apelin has been extensively described as a beneficial adipokine regarding to glucose and lipid metabolism and is endowed with anti-diabetic and anti-obesity properties. Indeed, there is a growing body of evi supporting apelin signaling as a novel promising therapeutic target for metabolic disorders (obesity, type 2 diabetes). In this review, we provide an overview of the pharmacological properties of APJ and its endogenous ligands. We also report the activity of peptidic and non peptidic agonists and antagonists targeting APJ described in the literature. Finally, we highlight the important role of this signaling pathway in the control of energy metabolism at the peripheral level and in the central nervous system in both physiological conditions and during obesity or diabetes. Copyright © 2015 Elsevier B.V. All rights reserved.
    European journal of pharmacology 05/2015; DOI:10.1016/j.ejphar.2015.05.017 · 2.53 Impact Factor
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    ABSTRACT: A wide range of adipokines identified over the past years has allowed considering the white adipose tissue as a secretory organ closely integrated into overall physiological and metabolic control. Apelin, a ubiquitously expressed peptide was known to exert different physiological effects mainly on the cardiovascular system and the regulation of fluid homeostasis prior to its characterization as an adipokine. This has broadened its range of action and apelin now appears clearly as a new player in energy metabolism in addition to leptin and adiponectin. Apelin has been shown to act on glucose and lipid metabolism but also to modulate insulin secretion. Moreover, different studies in both animals and humans have shown that plasma apelin concentrations are usually increased during obesity and type 2 diabetes. This mini-review will focus on the various systemic apelin effects on energy metabolism by addressing its mechanisms of action. The advances concerning the role of apelin in metabolic diseases in relation with the recent reports on apelin concentrations in obese and/or diabetic subjects will also be discussed.
    Frontiers in Physiology 04/2015; 6:115. DOI:10.3389/fphys.2015.00115 · 3.53 Impact Factor
  • Diabetes & Metabolism 03/2015; 41(4). DOI:10.1016/S1262-3636(15)30042-2 · 3.27 Impact Factor
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    ABSTRACT: The APJ receptor cloned in 1993 found its ligand in 1998 with the discovery of apelin. The presence of APJ in the central nervous system (more particularly in the hypothalamus) and in various tissues (heart, blood vessels, stomach, etc.) makes it a potential pharmacological target. Interest in APJ has allowed the development of peptidic molecules able to stimulate and/or inhibit the receptor and, more recently, to discover another endogenous ligand: apela. Among the functions regulated by the APJ/apelin system, the control of energy metabolism appears today in the forefront. A better understanding of the pharmacology of APJ receptor should allow innovative therapeutic approaches in the treatment of metabolic diseases. © 2015 médecine/sciences – Inserm.
    Medecine sciences: M/S 03/2015; 31(3):275-81. DOI:10.1051/medsci/20153103013 · 0.67 Impact Factor
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    Anne Drougard · Audren Fournel · Philippe Valet · Claude Knauf
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    ABSTRACT: Hypothalamus is a key area involved in the control of metabolism and food intake via the integrations of numerous signals (hormones, neurotransmitters, metabolites) from various origins. These factors modify hypothalamic neurons activity and generate adequate molecular and behavioral responses to control energy balance. In this complex integrative system, a new concept has been developed in recent years, that includes reactive oxygen species (ROS) as a critical player in energy balance. ROS are known to act in many signaling pathways in different peripheral organs, but also in hypothalamus where they regulate food intake and metabolism by acting on different types of neurons, including proopiomelanocortin (POMC) and agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons. Hypothalamic ROS release is under the influence of different factors such as pancreatic and gut hormones, adipokines (leptin, apelin,…), neurotransmitters and nutrients (glucose, lipids,…). The sources of ROS production are multiple including NADPH oxidase, but also the mitochondria which is considered as the main ROS producer in the brain. ROS are considered as signaling molecules, but conversely impairment of this neuronal signaling ROS pathway contributes to alterations of autonomic nervous system and neuroendocrine function, leading to metabolic diseases such as obesity and type 2 diabetes. In this review we focus our attention on factors that are able to modulate hypothalamic ROS release in order to control food intake and energy metabolism, and whose deregulations could participate to the development of pathological conditions. This novel insight reveals an original mechanism in the hypothalamus that controls energy balance and identify hypothalamic ROS signaling as a potential therapeutic strategy to treat metabolic disorders.
    Frontiers in Neuroscience 02/2015; 9:56. DOI:10.3389/fnins.2015.00056 · 3.66 Impact Factor
  • Nutrition Clinique et Métabolisme 12/2014; 28. DOI:10.1016/S0985-0562(14)70589-8 · 0.29 Impact Factor
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    ABSTRACT: During obesity, an hypoxic state develops within the adipose tissue resulting in insulin resistance. In order to understand the underlying mechanism, we analyzed the involvement of caveolae, since they play crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae, and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of Cavin-1 and -2 expression in the epididymal adipose tissue. Downregulation of expression of Cavins in response to hypoxia is dependent upon HIF-1. Indeed, inhibition of HIF-1 restores expression of Cavins and caveolae formation. Expression of Cavins regulates insulin signaling, since silencing of Cavin-1 and Cavin-2 impairs insulin signaling pathway. In human, Cavin-1 and -2 are decreased in the subcutaneous adipose tissue of obese diabetic patients compared to lean subjects. Moreover, the expression of Cavin-2 correlates negatively with HOMA-IR and HbA1c level. In conclusion, we propose a new mechanism where hypoxia inhibits Cavin-1 and Cavin-2 expression resulting in the disappearance of caveolae. This leads to the inhibition of insulin signaling and the establishment of insulin resistance.
    Endocrinology 12/2014; 156(3):en20141656. DOI:10.1210/en.2014-1656 · 4.50 Impact Factor
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    ABSTRACT: Background and purpose: Mitochondria-derived oxidative stress is believed to be crucially involved in cardiac ischaemia reperfusion (I/R) injury, although currently no therapies exist that specifically target mitochondrial reactive oxygen species (ROS) production. The present study was designed to evaluate the potential effects of the structural analogues of apelin-12, an adipocyte-derived peptide, on mitochondrial ROS generation, cardiomyocyte apoptosis, and metabolic and functional recovery to myocardial I/R injury. Experimental approach: In cultured H9C2 cardiomyoblasts and adult cardiomyocytes, oxidative stress was induced by hypoxia reoxygenation. Isolated rat hearts were subjected to 35 min of global ischaemia and 30 min of reperfusion. Apelin-12, apelin-13 and structural apelin-12 analogues, AI and AII, were infused during 5 min prior to ischaemia. Key results: In cardiac cells, mitochondrial ROS production was inhibited by the structural analogues of apelin, AI and AII, in comparison with the natural peptides, apelin-12 and apelin-13. Treatment of cardiomyocytes with AI and AII decreased cell apoptosis concentration-dependently. In a rat model of I/R injury, pre-ischaemic infusion of AI and AII markedly reduced ROS formation in the myocardial effluent and attenuated cell membrane damage. Prevention of oxidative damage by AI and AII was associated with the improvement of functional and metabolic recovery after I/R in the heart. Conclusions and implications: These data provide the evidence for the potential of the structural apelin analogues in selective reduction of mitochondrial ROS generation and myocardial apoptosis and form the basis for a promising therapeutic strategy in the treatment of oxidative stress-related heart disease.
    British Journal of Pharmacology 12/2014; 172(12). DOI:10.1111/bph.13038 · 4.84 Impact Factor
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    ABSTRACT: LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.
    Proceedings of the National Academy of Sciences 10/2014; 111(42). DOI:10.1073/pnas.1406107111 · 9.67 Impact Factor
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    ABSTRACT: Increasing evidence supports the critical roles played by adipose tissue in breast cancer progression. Yet, the mediators and mechanisms are poorly understood. Here, we show that breast cancer-associated adipose tissue from freshly isolated tumors promotes F-actin remodelling, cellular scattering, invasiveness and spheroid reorganization of cultured breast cancer cells. A combination of techniques including transcriptomics, proteomics and kinomics enabled us to identify paracrine secretion of oncostatin M (OSM) by cancer-associated adipose tissue. Specifically, OSM, expressed by CD45+ leucocytes in the stromal vascular fraction, induced phosphorylation of STAT3 (pSTAT3-)Y705 and S727 in breast cancer cells and transcription of several STAT3-dependent genes, including S100 family members S100A7, S100A8 and S100A9. Autocrine activation of STAT3 in MCF-7 cells ectopically expressing OSM induced cellular scattering and peritumoral neo-vascularization of orthotopic xenografts. Conversely, selective inhibition of OSM by neutralizing antibody and Jak family kinases by tofacitinib inhibited STAT3 signaling, peritumoral angiogenesis and cellular scattering. Importantly, nuclear staining of pSTAT3-Y705 identified at the tumor invasion front in ductal breast carcinomas correlates with increased lymphovascular invasion. Our work reveals the potential of novel therapeutic strategies targeting the OSM and STAT3 axis in breast cancer patients harboring nuclear pSTAT3-Y705.
    Cancer Research 09/2014; 74(23). DOI:10.1158/0008-5472.CAN-14-0160 · 9.33 Impact Factor
  • Annales Françaises d Anesthésie et de Réanimation 09/2014; 33:A165. DOI:10.1016/j.annfar.2014.07.277 · 0.84 Impact Factor
  • V. Laurent · L. Nieto · P. Valet · C. Muller
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    ABSTRACT: Outre les complications métaboliques, il est maintenant reconnu que l’obésité favorise la survenue et affecte le pronostic de nombreux cancers dont le cancer du sein. De nombreux arguments récents montrent que le cancer doit être considéré comme une maladie tissulaire dans laquelle les cellules cancéreuses interagissent de façon dynamique avec les cellules « normales » environnantes. Cette interaction dynamique repose sur un véritable cercle vicieux dans lequel les cellules cancéreuses vont modifier leur microenvironnement qui, en retour, va favoriser la croissance et la dissémination de la tumeur. Dans de nombreux cancers invasifs et en particuliers le cancer du sein, les cellules tumorales vont se retrouver à proximité du tissu adipeux (TA). Les adipocytes matures de part leur activité sécrétoire et métabolique sont tout à fait susceptibles de modifier le comportement de la tumeur. L’objectif de cette revue est donc de décrire dans un premier temps le rôle du microenvironnement dans la progression tumorale. Dans un second temps, nous verrons que les adipocytes péri-tumoraux acquièrent un phénotype spécifique et les mécanismes qui leur permettent d’amplifier l’agressivité tumorale. Dans l’obésité, le TA présente des modifications morphologiques et fonctionnelles qui pourraient le rendre plus enclin à favoriser localement la progression tumorale et expliquer le pronostic défavorable observé chez ces patients. Nous verrons donc dans une dernière partie les arguments précliniques qui permettent d’impliquer un effet paracrine du TA dans le lien entre obésité et aggravation de la progression tumorale chez les sujets obèses.
    Obésité 08/2014; 9(3):182-190. DOI:10.1007/s11690-014-0421-1
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    ABSTRACT: In mammals, birth entails complex metabolic adjustments essential for neonatal survival. Using a mouse knockout model, we identify crucial biological roles for the miR-379/miR-410 cluster within the imprinted Dlk1-Dio3 region during this metabolic transition. The miR-379/miR-410 locus, also named C14MC in humans, is the largest known placental mammal-specific miRNA cluster, whose 39 miRNA genes are expressed only from the maternal allele. We found that heterozygote pups with a maternal—but not paternal—deletion of the miRNA cluster display partially penetrant neonatal lethality with defects in the maintenance of energy homeostasis. This maladaptive metabolic response is caused, at least in part, by profound changes in the activation of the neonatal hepatic gene expression program, pointing to as yet unidentified regulatory pathways that govern this crucial metabolic transition in the newborn's liver. Not only does our study highlight the physiological importance of miRNA genes that recently evolved in placental mammal lineages but it also unveils additional layers of RNA-mediated gene regulation at the Dlk1-Dio3 domain that impose parent-of-origin effects on metabolic control at birth and have likely contributed to mammal evolution.
    The EMBO Journal 08/2014; 33(19). DOI:10.15252/embj.201387038 · 10.43 Impact Factor
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    ABSTRACT: Background/Objectives Impaired energy metabolism is the defining characteristic of obesity-related heart failure. The adipocyte-derived peptide apelin plays a role in the regulation of cardiovascular and metabolic homeostasis and may contribute to the link between obesity, energy metabolism and cardiac function. Here we investigate the role of apelin in the transition from metabolic adaptation to maladaptation of the heart in obese state.Methods Adult male C57BL/6 J, Apelin KO or wild-type mice were fed a high-fat diet (HFD) for 18 weeks. To induce heart failure mice were subjected to pressure overload after 18 weeks of HFD. Long-term effects of apelin on fatty acid (FA) oxidation, glucose metabolism, cardiac function and mitochondrial changes were evaluated in HFD-fed mice after 4 weeks of pressure overload. Cardiomyocytes from HFD-fed mice were isolated for analysis of metabolic responses.ResultsIn HFD-fed mice, pressure overload-induced transition from hypertrophy to heart failure is associated with reduced FA utilization (P<0.05), accelerated glucose oxidation (P<0.05) and mitochondrial damage. Treatment of HFD-fed mice with apelin for 4 weeks prevented pressure overload-induced decline in FA metabolism (P<0.05) and mitochondrial defects. Furthermore, apelin treatment lowered fasting plasma glucose (P<0.01), improved glucose tolerance (P<0.05) and preserved cardiac function (P<0.05) in HFD-fed mice subjected to pressure overload. In apelin KO HFD-fed mice, spontaneous cardiac dysfunction is associated with reduced FA oxidation (P<0.001) and increased glucose oxidation (P<0.05). In isolated cardiomyocytes, apelin stimulated FA oxidation in a dose-dependent manner and this effect was prevented by siRNA sirtuin 3 knock-down.Conclusion These data suggest that obesity-related decline in cardiac function is associated with defective myocardial energy metabolism and mitochondrial abnormalities. Furthermore, our work points for therapeutic potential of apelin to prevent myocardial metabolic abnormalities in heart failure paired with obesity.International Journal of Obesity accepted article preview online, 16 July 2014; doi:10.1038/ijo.2014.122.
    International journal of obesity (2005) 07/2014; 39(2). DOI:10.1038/ijo.2014.122 · 5.00 Impact Factor
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    ABSTRACT: Upper- and lower-body fat depots exhibit opposing associations with obesity-related metabolic disease. We defined the relationship between DXA-quantified fat depots and diabetes /cardiovascular risk factors in a healthy population-based cohort (n=3,399). Gynoid fat mass correlated negatively with insulin resistance after total fat mass adjustment whereas the opposite was seen for abdominal fat. Paired transcriptomic analysis of gluteal (GSAT) and abdominal subcutaneous adipose tissue (ASAT) was performed across the BMI spectrum (n=49; 21.4-45.5kg/m(2)). In both depots, "energy-generating metabolic" genes were negatively associated, and "inflammatory" genes were positively associated with obesity. However, associations were significantly weaker in GSAT. At the systemic level, arterio-venous release of the pro-inflammatory cytokine, interleukin-6 (n=34) was lower from GSAT than ASAT. Isolated preadipocytes retained a depot-specific transcriptional "memory" of embryonic developmental genes and exhibited differential promoter DNA methylation of selected genes (HOTAIR, TBX5) between GSAT and ASAT. shRNA-mediated silencing identified TBX5 as a regulator of preadipocyte proliferation and adipogenic differentiation in ASAT. In conclusion, intrinsic differences in the expression of developmental genes in regional adipocytes provide a mechanistic basis for diversity in adipose tissue function. The less inflammatory nature of lower-body adipose tissue offers insight into the opposing metabolic disease risk associations between upper- and lower-body obesity.
    Diabetes 06/2014; 63(11). DOI:10.2337/db14-0385 · 8.10 Impact Factor

Publication Stats

4k Citations
1,004.18 Total Impact Points


  • 1993–2015
    • Paul Sabatier University - Toulouse III
      • • Institut des Maladies Métaboliques et Cardiovasculaires de Toulouse - UMRS 1048 - I2MC
      • • Faculté de médecine Purpan
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1988–2015
    • French Institute of Health and Medical Research
      • • Institute of Metabolic and Cardiovascular Diseases I2MC
      • • Montpellier Cancer Research Institute IRCM
      Lutetia Parisorum, Île-de-France, France
    • CHU de Lyon - Groupement Hospitalier Edouard Herriot
      Lyons, Rhône-Alpes, France
  • 2008–2014
    • University of Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2008–2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2010
    • International Agency for Research on Cancer
      Lyons, Rhône-Alpes, France
  • 1987–2006
    • Centre Hospitalier Universitaire de Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2001
    • University of California, San Francisco
      • Department of Medicine
      San Francisco, California, United States
  • 2000
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 1989
    • Clinique médicale et pédagogique Dupré
      Île-de-France, France