Philippe Valet

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

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Publications (238)969.11 Total impact

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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 · 0.52 Impact Factor
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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
  • Nutrition Clinique et Métabolisme 12/2014; 28. DOI:10.1016/S0985-0562(14)70589-8 · 0.62 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 · 4.64 Impact Factor
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    ABSTRACT: Background And PurposeMitochondria-derived oxidative stress is believed to be centrally involved in cardiac ischemia-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, metabolic and functional recovery to myocardial I/R injury.Experimental ApproachIn cultured H9C2 cardiomyoblasts and adult cardiomyocytes oxidative stress was induced by hypoxia-reoxygenation. Isolated rat hearts were subjected to 35 minutes of global ischemia and 30 minutes of reperfusion. Apelin-12, apelin-13, structural apelin-12 analogues, AI and AII, were infused during 5 min prior to ischemia.Key ResultsIn cardiac cells, we demonstrated inhibition of mitochondrial ROS production by the structural analogues of apelin, AI and AII, in comparison with natural peptides, apelin-12 and apelin-13. Treatment of cardiomyocytes with AI and AII significantly decreased cell apoptosis in a dose-dependent manner. In a rat model of I/R injury, preischemic 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 to I/R in the heart.Conclusions And ImplicationsThese 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 diseases.
    British Journal of Pharmacology 12/2014; DOI:10.1111/bph.13038 · 4.99 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 · 9.81 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 · 9.28 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
  • 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; DOI:10.15252/embj.201387038 · 10.75 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 · 5.39 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 · 8.47 Impact Factor
  • Pancreatology 06/2014; 14(3):S68-S69. DOI:10.1016/j.pan.2014.05.612 · 2.50 Impact Factor
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    ABSTRACT: Adipose tissue is found in close proximity whith many invasive cancers. In breast cancer, early local tumour invasion results in close interactions of cancer cells with fully differentiated adipocytes. Aside from their energy-storing function, mature adipocytes are also active endocrine cells prone to influence tumour behaviour through heterotypic signaling processes. After a short description of anatomical depots specificities of adipose tissue, we describe the phenotypic changes induced by tumor secretion in tumour-surrounding adipocytes. These cells (that we named CAA for cancer-associated adipocytes) by their ability to secrete pro-inflammatory cytokines, extra-cellular matrix proteins and proteases involved in its remodeling, as well as to release free fatty acid, stimulate tumor proliferation, invasiveness and drug resistance. These results support the concept that adipocytes participate in a deleterious crosstalk with cancer cells to support tumour progression, that might be amplified in obesity conditions and explain the poor prognosis of cancers observed in this subset of patients.
    Medecine sciences: M/S 04/2014; 30(4):398-404. DOI:10.1051/medsci/20143004013 · 0.52 Impact Factor
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    Antioxidants & Redox Signaling 02/2014; DOI:10.1089/ars.2013.5182) · 7.67 Impact Factor
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    ABSTRACT: Background:Prader-Willi syndrome (PWS) results from abnormalities in the genomic imprinting process leading to hypothalamic dysfunction with an alteration of growth hormone (GH) secretion. PWS is associated with early morbid obesity and short stature which can be efficiently improved with GH treatment.Objectives:Our aims were to highlight adipose tissue structural and functional impairments in children with PWS and to study the modifications of those parameters on GH treatment.Subjects and methods:Plasma samples and adipose tissue biopsies were obtained from 23 research centers in France coordinated by the reference center for PWS in Toulouse, France. Lean controls (n=33), non-syndromic obese (n=53), untreated (n=26) and GH-treated PWS (n=43) children were enrolled in the study. Adipose tissue biopsies were obtained during scheduled surgeries from 15 lean control, 7 untreated and 8 GH-treated PWS children.Results:Children with PWS displayed higher insulin sensitivity as shown by reduced glycaemia, insulinemia and HOMA-IR compared with non-syndromic obese children. In contrast, plasma inflammatory cytokines such as TNF-α, MCP-1 and IL-8 were increased in PWS. Analysis of biopsies compared to control children revealed decreased progenitor cell content in the stromal vascular fraction of adipose tissue and an impairment of lipolytic response to β-adrenergic agonist in PWS adipocytes. Interestingly, both of these alterations in PWS seem to be ameliorated on GH treatment.Conclusion:Herein, we report adipose tissue dysfunctions in children with PWS which may be partially restored by GH treatment.International Journal of Obesity accepted article preview online, 10 January 2014. doi:10.1038/ijo.2014.3.
    International journal of obesity (2005) 01/2014; 38(9). DOI:10.1038/ijo.2014.3 · 5.39 Impact Factor
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    ABSTRACT: Hypothalamus is key area implicated in control of glucose homeostasis. This structure integrates nervous and peripheral informations to adapt a response modifying peripheral glucose utilization and maintaining energetic balance. Among peripheral signals, adipokines such as adiponectin and leptin are of special importance since deregulations of their actions are closely associated to metabolic disorders such as obesity and type 2 diabetes. During the past ten years, we have identified a new adipokine named apelin which has emerging role in the control of metabolism. The originality of the apelinergic system is to be largely represented in peripheral tissues (adipose tissue, intestine, etc.) and in the brain. Then, apelin is released by adipose tissue as all adipokines, but also present another crucial role as neurotransmitter in hypothalamic neurons. By acting in the whole body, apelin exerts pleiotropic actions and is now considered as a major determinant of physiological functions. Besides its general beneficial effects on peripheral targets, central action of apelin remains still a matter of debate. In this review, we have made a parallel between peripheral vs. central actions of apelin in term of signalization and effects. Then, we have focused our attention on hypothalamic apelin and its potential role in glucose metabolism and associated pathologies.
    Hormone and Metabolic Research 12/2013; 45(13):928-934. DOI:10.1055/s-0033-1351321 · 2.04 Impact Factor
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    ABSTRACT: Adipose tissue secretes various proteins referred to as adipokines, being involved in inflammation. It was recognized that mesenteric adipose tissue (MAT) is altered by inflammation, and pathologies such as inflammatory bowel disease (IBD). The aim of this study was to investigate the alterations of the mesenteric adipose tissue in two experimental colitis models in mice adapted to obtain moderate colonic inflammation. In mice, colonic inflammation was obtained using two models, i.e. DSS dissolved in drinking water or intra-colonic instillation of DNBS. Observations of the colon and IL-6 plasma level determination, demonstrated that DNBS treatment led to a stronger inflammation. The expression of adipokines (leptin and adiponectin) and inflammatory markers (IL-6, MCP-1, F4/80) was studied by qRT-PCR in the MAT of treated and control mice. Colitis induced a decrease of mRNA encoding to leptin, adiponectin in MAT. In contrast, colonic inflammation led to an increase of mRNA encoding to IL-6, MCP-1 and F4/80, a specific marker of macrophages. The mesenteric adipose tissue, in two models of moderate colitis, shows a loss of adipose profile and a strong increase of inflammatory pattern, close to the observations made in MAT of IBD patients. These data suggest that these pro-inflammatory modifications of MAT have to be taken into account in the pathophysiology of IBD.
    Life sciences 11/2013; DOI:10.1016/j.lfs.2013.09.028 · 2.30 Impact Factor
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    ABSTRACT: Various studies have shown that eicosapentaenoic acid (EPA) has beneficial effects on obesity and associated disorders. Apelin, the ligand of APJ receptor also exerts insulin-sensitizing effects especially by improving muscle metabolism. EPA has been shown to increase apelin production in adipose tissue but its effects in muscle have not been addressed. Thus, the effects of EPA supplementation (36 g/kg EPA) in high-fat diet (HFD) (45% fat, 20% protein, 35% carbohydrate) were studied in mice with focus on muscle lipid metabolism and apelin/APJ expression. Compared with HFD mice, HFD+EPA mice had significantly less weight gain, fat mass, lower blood glucose, insulinemia and hepatic steatosis after 10 weeks of diet. In addition, EPA prevented muscle metabolism alterations since intramuscular triglycerides were decreased and β-oxidation increased. In soleus muscles of HFD+EPA mice, apelin and APJ expression were significantly increased compared to HFD mice. However, plasma apelin concentrations in HFD and HFD+EPA mice were similar. EPA-induced apelin expression was confirmed in differentiated C2C12 myocytes but in this model, apelin secretion was also increased in response to EPA treatment. In conclusion, EPA supplementation in HFD prevents obesity and metabolic alterations in mice, especially in skeletal muscle. Since EPA increases apelin/APJ expression in muscle, apelin may act in a paracrine/autocrine manner to contribute to these benefical effects.
    PLoS ONE 11/2013; 8(11):e78874. DOI:10.1371/journal.pone.0078874 · 3.53 Impact Factor

Publication Stats

4k Citations
969.11 Total Impact Points


  • 1995–2015
    • 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
  • 1995–2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2010
    • International Agency for Research on Cancer
      Lyons, Rhône-Alpes, France
  • 1988–2006
    • Centre Hospitalier Universitaire de Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2005
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
  • 2004
    • Universidad de Salamanca
      Helmantica, Castille and León, Spain
  • 2002
    • Charles University in Prague
      • Department of Sport Medicine (3. LF)
      Praha, Praha, Czech Republic
  • 2001
    • University of California, San Francisco
      • Department of Medicine
      San Francisco, California, United States
  • 2000
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1989
    • Clinique médicale et pédagogique Dupré
      Île-de-France, France
  • 1987
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France