Philippe Valet

French Institute of Health and Medical Research, Lutetia Parisorum, Île-de-France, France

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Publications (225)898.61 Total impact

  • Nutrition Clinique et Métabolisme 12/2014; 28. · 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; · 4.72 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; · 5.07 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 of the United States of America. 10/2014;
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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; · 9.28 Impact Factor
  • Annales Françaises d Anesthésie et de Réanimation 09/2014; 33:A165. · 0.84 Impact Factor
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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; · 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; · 5.22 Impact Factor
  • Pancreatology 06/2014; 14(3):S68-S69. · 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. · 0.52 Impact Factor
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    Antioxidants & Redox Signaling 02/2014; · 8.20 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; · 5.22 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. · 2.15 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; · 2.56 Impact Factor
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    ABSTRACT: Lipopolysaccharides (LPS) of the cell wall of Gram (-) bacteria trigger inflammation, which is associated with marked changes in glucose metabolism. Hyperglycemia is frequently observed during bacterial infection and it is a marker of a poor clinical outcome in critically ill patients. The aim of the present study was to investigate the effect of an acute injection or continuous infusion of LPS on experimentally-induced hyperglycemia in wild-type and genetically-engineered mice. The acute injection of a single dose of LPS produced an increase in glucose disposal and glucose-stimulated insulin secretion (GSIS). Continuous infusion of LPS through mini-osmotic pumps was also associated with increased GSIS. Finally, manipulation of LPS detoxification by knocking out the plasma phospholipid transfer protein (PLTP) led to increased glucose disposal and GSIS. Overall, glucose tolerance and GSIS tests supported the hypothesis that mice treated with LPS develop glucose-induced hyperinsulinemia. The effects of LPS on glucose metabolism were significantly altered as a result of either the accumulation or antagonism of glucagon-like peptide 1 (GLP1). Complementary studies in wild-type and GLP1-R knockout mice further implicated the GLP1R-dependent pathway in mediating the LPS-mediated changes in glucose metabolism. Hence, enhanced GLP1 secretion and action underlies the development of glucose-mediated hyperinsulinemia associated with endotoxemia.
    Diabetes 11/2013; · 7.90 Impact Factor
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    ABSTRACT: Lysophosphatidic acid (LPA) is a pro-fibrotic mediator acting via specific receptors (LPARs) and is synthesized by autotaxin, which expression is increased in obesity. We tested whether LPA could play a role in adipose tissue (AT)-fibrosis associated with obesity. Fibrosis [type I, III, and IV collagens (COL), fibronectin (FN), TGFβ, CTGF and αSMA] and inflammation (MCP1 and F4/80) markers were quantified: (i) in vivo in inguinal (IAT) and perigonadic (PGAT) AT from obese-diabetic db/db mice treated with the LPAR antagonist Ki16425 (5mg/kg/day ip for 7weeks); and (ii) in vitro in human AT explants in primary culture for 72h in the presence of oleoyl-LPA (10μM) and/or Ki16425 (10μM) and/or the HIF-1α inhibitor YC-1 (100μM). Treatment of db/db mice with Ki16425 reduced COL I and IV mRNAs in IAT and PGAT while COL III mRNAs were only reduced in IAT. This was associated with reduction of COL protein staining in both IAT and PGAT. AT explants showed a spontaneous and time-dependent increase in ATX expression and production of LPA in the culture medium, along with increased levels of COL I and III, TGFβ and αSMA mRNAs and of COL protein staining. In vitro fibrosis was blocked by Ki16425 and was further amplified by oleoyl-LPA. LPA-dependent in vitro fibrosis was blocked by co-treatment with YC1. Our results show that endogenous and exogenous LPA exert a pro-fibrotic activity in AT in vivo and in vitro. This activity could be mediated by an LPA1R-dependent pathway and could involve HIF-1α.
    Biochimica et Biophysica Acta 10/2013; · 4.66 Impact Factor
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    ABSTRACT: IntroductionIt has been suggested that metabolic benefits of physical exercise could be mediated by myokines. We examined here the effect of exercise training on skeletal muscle expression of a panel of myokines in humans. Pathways regulating myokine expression were investigated in human myotubes.Methods Eleven obese non diabetic male subjects were enrolled in an 8-week endurance training program. Insulin sensitivity was assessed by oral glucose tolerance test. Subcutaneous adipose tissue and Vastus Lateralis muscle biopsies were collected before and after training. RNAs were prepared from adipose tissue and skeletal muscle. Primary culture of myoblasts was established.ResultsAs expected, exercise training improved aerobic capacity and decreased fat mass. No significant change in interleukin 6, fibroblast growth factor 21, myostatin or irisin mRNA level was found in muscle after training. A 2-fold increase in apelin mRNA level was found in muscle but not in adipose tissue. No change in circulating myokine and adipokine plasma levels was observed in the resting state in response to training. Interestingly, apelin was significantly expressed and secreted in primary human myotubes. Apelin gene expression was up-regulated by cyclic AMP and calcium unlike the other myokines investigated. Importantly, muscle apelin mRNA levels were positively related to whole-body insulin sensitivity.Conclusion Collectively, our data show that exercise training up-regulates muscle apelin expression in obese subjects. Apelin expression is induced by exercise signalling pathways and secreted in vitro in human primary myotubes, and may behave as a novel exercise-regulated myokine with autocrine/paracrine action.International Journal of Obesity accepted article preview online, 27 August 2013. doi:10.1038/ijo.2013.158.
    International journal of obesity (2005) 08/2013; · 5.22 Impact Factor
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    ABSTRACT: Apelin is an enteric peptide that exerts several digestive functions such as stimulation of cell proliferation and cholecystokinin (CCK) secretion. We investigated using murine enteroendocrine cell line (STC-1) and rats if apelin-13 stimulates both CCK and glucagon-like peptide 1 (GLP-1) secretions. We demonstrated that, in vitro and in vivo, apelin-13 increases the release of these two hormones in a dose-dependent manner. Present data suggest that apelin may modulate digestive functions, food intake behavior and glucose homoeostasis via apelin-induced release of enteric CCK but also through a new incretin-releasing activity on enteric GLP-1.
    Peptides 08/2013; · 2.61 Impact Factor
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    ABSTRACT: Metabolic endotoxemia triggers inflammation, targets cells from the stroma-vascular fraction of adipose depots, and metabolic disease. To identify these cells we here infused mice with lipopolysaccharides and showed by FACS analyses and BrdU staining that the number of small subcutaneous adipocytes, preadipocytes and macrophages increased in wild type but not in CD14-knockout (KO) mice. This mechanism was direct since in CD14KO mice grafted subcutaneously and simultaneously with fat pads from CD14KO and wild-type mice the concentration of cytokine mRNA was increased in the wild-type fat pad only. Conversely, the mRNA concentration of genes involved in glucose and lipid metabolism and the number of large adipocytes was reduced. Eventually, a pretreatment with LPS enhanced HFD-induced metabolic diseases. Altogether, these results show that metabolic endotoxemia increases the proliferation of preadipocytes through a CD14-dependent mechanism directly, without recruiting CD14-positive cells from non-adipose depot origin. This mechanism could precede the onset of metabolic diseases.
    Molecular metabolism. 08/2013; 2(3):281-91.
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    ABSTRACT: Cancer-associated fibroblasts (CAFs) comprise the majority of stromal cells in breast cancers, yet their precise origins and relative functional contributions to malignant progression remain uncertain. Local invasion leads to the proximity cancer cells and adipocytes, which respond by phenotypical changes to generate fibroblast-like cells termed here adipocyte-derived fibroblasts (ADFs). These cells exhibit enhanced secretion of fibronectin and collagen I, increased migratory/invasive abilities and increased expression of the CAF marker FSP-1 but not αSMA. Generation of the ADF phenotype depends on reactivation of the Wnt/β-catenin pathway in response to Wnt3a secreted by tumor cells. Tumor cells co-cultivated with ADFs in 2D or spheroid culture display increased invasive capabilities. In clinical specimens of breast cancer, we confirmed the presence of this new stromal sub-population. By defining a new stromal cell population, our results offer new opportunities for stroma-targeted therapies in breast cancer.
    Cancer Research 07/2013; · 9.28 Impact Factor

Publication Stats

3k Citations
898.61 Total Impact Points

Institutions

  • 1988–2014
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2012–2013
    • University of Lille Nord de France
      Lille, Nord-Pas-de-Calais, France
  • 1995–2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2008–2012
    • University of Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1990–2012
    • Paul Sabatier University - Toulouse III
      • • Institut des Maladies Métaboliques et Cardiovasculaires de Toulouse - UMRS 1048 - I2MC
      • • Faculté de médecine Purpan
      Toulouse, Midi-Pyrenees, France
  • 2011
    • Imperial College London
      • Department of Surgery and Cancer
      London, ENG, United Kingdom
  • 2006
    • Universidad de Salamanca
      • Departamento de Fisiología y Farmacología
      Salamanca, Castile and Leon, Spain
  • 1987–2006
    • Centre Hospitalier Universitaire de Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2005
    • Institut Louis Bachelier
      Lutetia Parisorum, Île-de-France, France
  • 2000
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1989
    • Clinique médicale et pédagogique Dupré
      Île-de-France, France