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32 results on '"MESH: 3T3-L1 Cells"'

1. Identification of adipocytes as target cells for Leishmania infantum parasites

Author: Schwing, Aurélie, Pisani, Didier, Pomares, Christelle, Majoor, Alissa, Lacas-Gervais, Sandra, Jager, Jennifer, Lemichez, Emmanuel, Marty, Pierre, Boyer, Laurent, Michel, Grégory, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Aix Marseille Université (AMU), Laboratoire de PhysioMédecine Moléculaire (LP2M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), CCMA - Centre Commun de Microscopie Appliquée, Université Côte d'Azur (UCA), Toxines bactériennes - Bacterial Toxins, Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), We acknowledge financial support by the Conseil Départemental des Alpes-Maritimes and Conseil Régional PACA. This work was supported by a Grant from the Société Francophone du Diabète (SFD)/Pierre Fabre Médicament 2017., and DELARUE, NADINE
Subjects: Parasitic infection, Science, [SDV]Life Sciences [q-bio], MESH: Disease Susceptibility, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Article, Host-Parasite Interactions, Mice, MESH: Psychodidae, 3T3-L1 Cells, parasitic diseases, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Adipocytes, Parasite immune evasion, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, MESH: Animals, Leishmania infantum, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, MESH: 3T3-L1 Cells, MESH: Leishmania infantum, [SDV] Life Sciences [q-bio], Disease Models, Animal, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Adipose Tissue, MESH: Leishmaniasis, Visceral, Medicine, Leishmaniasis, Visceral, Disease Susceptibility, Psychodidae, MESH: Disease Models, Animal, MESH: Adipose Tissue
Abstract: International audience; Leishmania infantum is the causative agent of visceral leishmaniasis transmitted by the bite of female sand flies. According to the WHO, the estimated annual incidence of leishmaniasis is one million new cases, resulting in 30,000 deaths per year. The recommended drugs for treating leishmaniasis include Amphotericin B. But over the course of the years, several cases of relapses have been documented. These relapses cast doubt on the efficiency of actual treatments and raise the question of potential persistence sites. Indeed, Leishmania has the ability to persist in humans for long periods of time and even after successful treatment. Several potential persistence sites have already been identified and named as safe targets. As adipose tissue has been proposed as a sanctuary of persistence for several pathogens, we investigated whether Leishmania infantum could be found in this tissue. We demonstrated both in cell cultures and in vivo that Leishmania infantum was able to infect adipocytes. Altogether our results suggest adipocytes as a ‘safe target’ for Leishmania infantum parasites.
Published: 2021
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2. Gene Expression Pattern in Response to Cholecalciferol Supplementation Highlights Cubilin as a Major Protein of 25(OH)D Uptake in Adipocytes and Male Mice White Adipose Tissue

Author: Catherine Defoort, Esma Karkeni, Lauriane Bonnet, Jean-François Landrier, Jean-Charles Martin, Charlène Couturier, Julie Dalifard, Franck Tourniaire, Ljubica Svilar, Julien Astier, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre recherche en CardioVasculaire et Nutrition (C2VN)
Subjects: 0301 basic medicine, Male, Adipose tissue, White adipose tissue, Calcitriol receptor, chemistry.chemical_compound, Mice, Endocrinology, Adipocyte, Gene expression, Adipocytes, polycyclic compounds, Vitamin D, Cells, Cultured, Cholecalciferol, MESH: Adipocytes/drug effects, MESH: Adipocytes/metabolism, Female, lipids (amino acids, peptides, and proteins), MESH: Adipose Tissue, White/drug effects, medicine.medical_specialty, Adipose Tissue, White, Receptors, Cell Surface, Biology, 03 medical and health sciences, Internal medicine, 3T3-L1 Cells, medicine, Vitamin D and neurology, Animals, Humans, Nutrition, VDR, Gene Expression Profiling, MESH: Adipose Tissue, White/metabolism, adipocyte, tissu adipeux, souris, protéine majeure, expression génique, expression des gènes, analyse transcriptionnelle, Cubilin, Lipid Metabolism, MESH: 3T3-L1 Cells, Mice, Inbred C57BL, 030104 developmental biology, Metabolism, chemistry, Gene Expression Regulation, Dietary Supplements, Receptors, Calcitriol, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: International audience; It is well established that the active form of vitamin D (i.e., 1,25-dihydroxyvitamin D [1,25(OH)2D]) regulates the expression of genes involved in its own metabolism and transport in the kidney and possibly in the liver. However, little is known about the transcriptional impact of cholecalciferol supplementation on white adipose tissue (WAT) and adipocytes, which are a major site of vitamin D and 25-hydroxyvitamin D [25(OH)D] storage in the organism. To fill this gap, we investigated the impact of cholecalciferol supplementation in WAT via a panel of genes coding for enzymes and proteins involved in vitamin D metabolism and uptake. Mice supplemented with cholecalciferol (15,000 IU/kg of body weight per day) for 4 days showed decreased messenger RNA (mRNA) levels of proteins involved in cholecalciferol metabolism (Cyp24a1, Cyp27a1) and decreased cubilin mRNA levels in WAT. These data were partly confirmed in 3T3-L1 adipocytes incubated with 1,25(OH)2D. The downregulation of cubilin mRNA observed in WAT and in 3T3-L1 was confirmed at the protein level in WAT and at the mRNA level in human primary adipocytes. Vitamin D receptor (VDR) agonist (EB1089) and RNA interference approaches demonstrated that VDR was involved in this regulation. Furthermore, chemical inhibitor and RNA inference analysis demonstrated that cubilin was involved in 25(OH)D uptake by adipocytes. This study established an overall snapshot of the genes regulated by cholecalciferol in mouse WAT and cell-autonomously in adipocytes. We highlighted that the regulation of cubilin expression was mediated by a VDR-dependent mechanism, and we demonstrated that cubilin was involved in 25(OH)D uptake by adipocytes.
Published: 2018
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3. Peroxisome Proliferator-activated Receptor γ Regulates Genes Involved in Insulin/Insulin-like Growth Factor Signaling and Lipid Metabolism during Adipogenesis through Functionally Distinct Enhancer Classes

Author: Stéphane Avner, Philippe Froguel, Bart Staels, Gilles Salbert, Philippe Lefebvre, Frédérik Oger, Jérôme Eeckhoute, Julie Dubois-Chevalier, Emmanuelle Durand, Céline Gheeraert, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Subjects: Epigenomics, MESH: Signal Transduction, Muscle Fibers, Skeletal, Peroxisome proliferator-activated receptor, Enhancer RNAs, Biochemistry, Mice, chromatin modification, Transcrip tion regulation, MESH: Reverse Transcriptase Polymerase Chain Reaction, DNA methylat ion, MESH: Gene Expression Regulation, Developmental, Adipocytes, Insulin, MESH: Animals, insulin/insulin-like growth factor signalling, MESH: Lipid Metabolism, MESH: Chromatin Immunoprecipitation, chemistry.chemical_classification, Adipogenesis, MESH: Muscle Fibers, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Regulation, Developmental, Enhancer Elements, Genetic, Signal transduction, Transcription enhancers, Protein Binding, Signal Transduction, Chromatin Immunoprecipitation, MESH: Insulin, Biology, Cell Line, Somatomedins, 3T3-L1 Cells, Animals, MESH: Protein Binding, Gene Regulation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Somatomedins, Enhancer, MESH: Mice, Molecular Biology, Transcription factor, MESH: Adipocytes, MESH: Transcriptome, Lipid metabolism, Cell Biology, Lipid Metabolism, MESH: 3T3-L1 Cells, MESH: Cell Line, PPAR gamma, MESH: PPAR gamma, Nuclear receptor, chemistry, Peroxisome proliferator-activated receptor (PPAR), MESH: Enhancer Elements, Genetic, Transcriptome, MESH: Adipogenesis
Abstract: International audience; The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPAR induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPAR also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPAR utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process.
Published: 2014
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4. DNA damage and the activation of the p53 pathway mediate alterations in metabolic and secretory functions of adipocytes Running title: DNA damage and p53 in obese adipocytes

Author: Vergoni, Bastien, Cornejo, Pierre-Jean, Gilleron, Jérôme, Dedjani, Mansour, Ceppo, Franck, Jacquel, Arnaud, Bouget, Gwennaelle, Ginet, Clémence, Gonzalez, Teresa, Maillet, Julie, Dhennin, Véronique, Verbanck, Marie, Auberger, Patrick, Froguel, Philippe, Tanti, Jean-François, Cormont, Mireille, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cellulaire et Moléculaire de l'Obésité et du Diabète (Equipe 7), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Mort cellulaire, différenciation et cancer (Equipe 2), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-C3M - Centre Méditerranéen de Médecine Moléculaire, Hôpital l'Archet - CHU de Nice-Hôpital l'Archet - CHU de Nice, Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Department of Genomics of Common Disease [London, UK], Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), This work was supported by INSERM, the Université Côte d'Azur, and by grants from the European Foundation for the Study of Diabetes (EFSD/Lilly), SFD-Abbott, Aviesan/AstraZeneca (Diabetes and the Vessel Wall Injury Program), and the French National Research Agency (ANR) through 'Investments for the Future' Labex SIGNALIFE (grant ANR-11-LABX-0028-01). Light microscopy was performed at the C3M Imaging core facility (part of the Microscopy and Imaging platform Côte d’Azur IBISA). The Nikon A1R-FLIM microscope used for this study was funded thanks to Conseil Général Alpes-Maritimes ('Appel à Projets Santé') and by Région Provence-Alpes-Côte d'Azur (PACA) ('Appel à Projets Plateforme'). The UMR 8199 Genotyping and Expression platform (Lille, France) belongs to the 'Federation de Recherche' 3508 funded by Labex EGID (European Genomics Institute for Diabetes, ANR-10-LABX-46) and by the ANR Equipex 2010 session (ANR-10-EQPX-07-01, 'LIGAN-PM'). The LIGAN-PM Genomics platform (Lille, France) is also supported by the Fonds Européen de Développement Régional (FEDR) and the Region Nord-Pas-de-Calais-Picardie. B.V. and P.-J.C. were supported by the French Ministry of Education and Research. J.G. was supported by a fellowship (postdoctoral grant) from the 'Fondation pour la Recherche Médicale.' F.C. was supported by a fellowship from INSERM/Région PACA/FEDER (PhD grant) and by a grant from the Société Francophone du Diabète (SFD/Abbott). G.B. was supported by the Labex SIGNALIFE grant (ANR-11-LABX-0028-01). J.-F.T. is an investigator of the CNRS., The authors thank the animal facility staff for animal care and breeding, Damien Alcor, head of the Cell Imaging core facility (INSERM UMR 1065, C3M, Nice, France), and also Prof. Marino Zerial and Dr. Yannis Lalaiszidis (Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany) for the free access to the motion-tracking software developed in Prof. Zerial’s laboratory., ANR: 11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-10-LABX-0046/10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-10-EQPX-07-01 ,[LIGAN-PM],ANR Equipex 2010 session, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-C3M - Centre Méditerranéen de Médecine Moléculaire, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-10-EQPX-0007,LIGAN PM,Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée(2010), ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cormont, Mireille, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée - - LIGAN PM2010 - ANR-10-EQPX-0007 - EQPX - VALID, and Idex UCA JEDI - - UCA JEDI2015 - ANR-15-IDEX-0001 - IDEX - VALID
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Signal Transduction/physiology, MESH: Humans, MESH: DNA Damage/genetics, MESH: Flow Cytometry, MESH: Chemotaxis/physiology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Reactive Oxygen Species/metabolism, MESH: 3T3-L1 Cells, MESH: Chemotaxis/genetics, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, MESH: Glucose Transporter Type 4/metabolism, MESH: Glucose Transporter Type 4/genetics, MESH: Telomere/genetics, MESH: Tumor Suppressor Protein p53/genetics, MESH: DNA Damage/physiology, MESH: Blotting, Western, MESH: RAW 264.7 Cells, MESH: Animals, MESH: Signal Transduction/genetics, MESH: Tumor Suppressor Protein p53/metabolism, MESH: Adipocytes/metabolism, MESH: Fluorescent Antibody Technique, MESH: Mice, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: International audience; Activation of the p53 pathway in adipose tissue contributes to insulin resistance associated with obesity. However, the mechanisms of p53 activation and the impact on adipocyte functions are still elusive. Here we found a higher level of DNA oxidation and a reduction in telomere length in adipose tissue of high-fat diet mice and an increase in DNA damage and activation of the p53 pathway in adipocytes. Interestingly, hallmarks of chronic DNA damage are visible at the onset of obesity. Furthermore, treatment of lean mice with doxorubicin, a DNA damage-inducing drug, increased the expression of chemokines in adipose tissue and promoted its infiltration by pro-inflammatory macrophages and neutrophils together with adipocyte insulin resistance. In vitro, DNA damage in adipocytes increased chemokines expression and triggered the production of chemotactic factors for macrophages and neutrophils. Insulin signaling and effect on glucose uptake and Glut4 translocation were decreased while lipolysis was increased. These events were prevented by p53 inhibition whereas its activation by nutlin-3 reproduced the DNA damage-induced adverse effects. This study reveals that DNA damage in obese adipocyte could trigger p53-dependent signals involved in alteration of adipocyte metabolism and secretory function leading to adipose tissue inflammation, adipocyte dysfunction and insulin resistance.
Published: 2016
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5. A Possible Inflammatory Role of Twist1 in Human White Adipocytes

Author: Amanda T. Pettersson, Anne Bouloumié, Mikael Rydén, Peter Arner, Ingrid Dahlman, Niklas Mejhert, Jurga Laurencikiene, Erik Näslund, Simon, Marie Francoise, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Division of Surgery, Department of Clinical Sciences, Karolinska Institutet [Stockholm]-Danderyds sjukhus = Danderyd University Hospital, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, MESH: Oxidation-Reduction, Small interfering RNA, Endocrinology, Diabetes and Metabolism, Cellular differentiation, Adipocytes, White, Palmitates, Gene Expression, Adipose tissue, White adipose tissue, MESH: Down-Regulation, Mice, chemistry.chemical_compound, 0302 clinical medicine, Genes, Reporter, Adipocyte, MESH: RNA, Small Interfering, Gene expression, MESH: Animals, Carbon Radioisotopes, RNA, Small Interfering, Promoter Regions, Genetic, MESH: Carbon Radioisotopes, Beta oxidation, Chemokine CCL2, 0303 health sciences, MESH: Middle Aged, Nuclear Proteins, MESH: Twist Transcription Factor, Middle Aged, MESH: Adiponectin, Cell biology, 030220 oncology & carcinogenesis, Original Article, Female, Adiponectin, Oxidation-Reduction, Adult, medicine.medical_specialty, MESH: Gene Expression, animal structures, Lipolysis, Down-Regulation, Biology, 03 medical and health sciences, 3T3-L1 Cells, Internal medicine, MESH: Promoter Regions, Genetic, Internal Medicine, medicine, Animals, Humans, MESH: Lipolysis, MESH: Mice, MESH: Chemokine CCL2, 030304 developmental biology, MESH: Humans, Interleukin-6, Tumor Necrosis Factor-alpha, Twist-Related Protein 1, MESH: Genes, Reporter, MESH: Adult, MESH: Palmitates, MESH: Interleukin-6, MESH: 3T3-L1 Cells, MESH: Male, MESH: Adipocytes, White, Metabolism, Endocrinology, chemistry, MESH: Tumor Necrosis Factor-alpha, MESH: Nuclear Proteins, MESH: Female
Abstract: OBJECTIVE Twist1 is a transcription factor that is highly expressed in murine brown and white adipose tissue (WAT) and negatively regulates fatty acid oxidation in mice. The role of twist1 in WAT is not known and was therefore examined. RESEARCH DESIGN AND METHODS The expression of twist1 was determined by quantitative real-time PCR in different tissues and in different cell types within adipose tissue. The effect of twist1 small interfering RNA on fatty acid oxidation, lipolysis, adipokine secretion, and mRNA expression was determined in human adipocytes. The interaction between twist1 and specific promoters in human adipocytes was investigated by chromatin immunoprecipitation (ChIP) and reporter assays. RESULTS Twist1 was highly expressed in human WAT compared with a set of other tissues and found predominantly in adipocytes. Twist1 levels increased during in vitro differentiation of human preadipocytes. Gene silencing of twist1 in human white adipocytes had no effect on lipolysis or glucose transport. Unexpectedly, and in contrast with results in mice, twist1 RNA interference reduced fatty acid oxidation. Furthermore, the expression and secretion of the inflammatory factors tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 were downregulated by twist1 silencing. ChIP and reporter assays confirmed twist1 interaction with the promoters of these genes. CONCLUSIONS Twist1 may play a role in inflammation of human WAT because it can regulate the expression and secretion of inflammatory adipokines via direct transcriptional effects in white adipocytes. Furthermore, twist1 may, in contrast to findings in mice, be a positive regulator of fatty acid oxidation in human white adipocytes.
Published: 2009
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6. Interleukin-1β-Induced Insulin Resistance in Adipocytes through Down-Regulation of Insulin Receptor Substrate-1 Expression

Author: Mireille Cormont, T Grémeaux, Jennifer Jager, Yannick Le Marchand-Brustel, Jean-François Tanti, Tanti, Jean-François, Signalisation moléculaire et obésité, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), This work is part of the project 'Hepatic and adipose tissue and functions in the metabolic syndrome' (HEPADIP, see http://www.hepadip.org/), which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005-018734), and Université Nice Sophia Antipolis (... - 2019) (UNS)
Subjects: MESH: Inflammation, medicine.medical_treatment, Interleukin-1beta, Gene Expression, Mice, Obese, MESH: GTPase-Activating Proteins, MESH: Down-Regulation, Mice, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Insulin receptor substrate, Adipocytes, MESH: Animals, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, MESH: Extracellular Signal-Regulated MAP Kinases, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Glucose Transporter Type 1, 0303 health sciences, Glucose Transporter Type 4, biology, GTPase-Activating Proteins, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Glucose, MESH: Insulin Resistance, medicine.medical_specialty, MESH: Gene Expression, Insulin Receptor Substrate Proteins, MAP Kinase Signaling System, Down-Regulation, 030209 endocrinology & metabolism, Article, 03 medical and health sciences, Insulin resistance, Downregulation and upregulation, 3T3-L1 Cells, Internal medicine, medicine, Animals, MESH: Adipocytes, 030304 developmental biology, Inflammation, Interleukin-6, MESH: Interleukin-1be, Insulin, Tyrosine phosphorylation, Phosphoproteins, medicine.disease, MESH: 3T3-L1 Cells, IRS1, Insulin receptor, Glucose, chemistry, biology.protein, Tyrosine, MESH: Glucose Transporter Type 4, Insulin Resistance, Proto-Oncogene Proteins c-akt, MESH: Glucose Transporter Type 1
Abstract: Inflammation is associated with obesity and insulin resistance. Proinflammatory cytokines produced by adipose tissue in obesity could alter insulin signaling and action. Recent studies have shown a relationship between IL-1beta level and metabolic syndrome or type 2 diabetes. However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. We demonstrated that IL-1beta slightly increased Glut 1 translocation and basal glucose uptake in 3T3-L1 adipocytes. Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. Chronic treatment with IL-1beta slightly decreased the expression of Glut 4 and markedly inhibited its translocation to the plasma membrane in response to insulin. This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes.
Published: 2007
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7. The Paired Basic Amino Acid-cleaving Enzyme 4 (PACE4) Is Involved in the Maturation of Insulin Receptor Isoform B: an opportunity to reduce the specific insulin receptor-dependent effects of insulin-like growth factor 2 (IGF2)

Author: Kara, Imène, Poggi, Marjorie, Bonardo, Bernadette, Govers, Roland, Landrier, Jean-François, Tian, Sun, Leibiger, Ingo, Day, Robert, Creemers, John W. M., Peiretti, Franck, peiretti, franck, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Amsterdam, The Netherlands, Karolinska Institutet [Stockholm], Université de Sherbrooke (UdeS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), INSERM, INRA, Aix-Marseille Universite, Ministere de la Recherche et de l'Enseignement Superieur, Prostate Cancer Canada [D2013-8, 2012-951, TAG2014-02], Canadian Cancer Society Research Institute [701590], and Fonds Wetenschappelijk Onderzoek (FWO) Vlaanderen
Subjects: animal structures, MESH: Receptor, Insulin, Insulin-like Growth Factor (IGF), viruses, Insulin Receptor, MESH: Furin, Mitogenic Signaling, MESH: Insulin-Like Growth Factor II, Cell Signaling, MESH: Cell Proliferation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Serine Endopeptidases, MESH: Mice, health care economics and organizations, Furin, MESH: Humans, MESH: Immunoblotting, MESH: Real-Time Polymerase Chain Reaction, Metabolic Signaling, Proprotein Convertase, humanities, MESH: 3T3-L1 Cells, MESH: HEK293 Cells, MESH: HeLa Cells, MESH: Proprotein Convertases
Abstract: International audience; Background: The insulin receptor exists as two isoforms: IRA and IRB. Results: IRA and IRB are similarly matured by furin, but when furin activity is reduced, IRB is matured by PACE4. Conclusion: Proprotein convertase inhibition can selectively reduce IRA maturation and its signaling. Significance: This can be considered as a new opportunity to target IRA signaling in cancer. Gaining the full activity of the insulin receptor (IR) requires the proteolytic cleavage of its proform by intra-Golgi furin-like activity. In mammalian cells, IR is expressed as two isoforms (IRB and IRA) that are responsible for insulin action. However, only IRA transmits the growth-promoting and mitogenic effects of insulin-like growth factor 2. Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation. Therefore, in situations of impaired furin activity, the proteolytic maturation of IRB is greater than that of IRA, and accordingly, the amount of phosphorylated IRB is also greater than that of IRA. We highlight the ability of a particular proprotein convertase inhibitor to effectively reduce the maturation of IRA and its associated mitogenic signaling without altering the signals emanating from IRB. In conclusion, the selective PACE4-dependent maturation of IRB occurs when furin activity is reduced; accordingly, the pharmacological inhibition of furin reduces IRA maturation and its mitogenic potential without altering the insulin effects.
Published: 2015
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8. The Paired Basic Amino Acid-cleaving Enzyme 4 (PACE4) Is Involved in the Maturation of Insulin Receptor Isoform B

Author: Kara, Imène, Poggi, Marjorie, Bonardo, Bernadette, Govers, Roland, Landrier, Jean-François, Tian, Sun, Leibiger, Ingo, Day, Robert, Creemers, John W. M., Peiretti, Franck, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Amsterdam, The Netherlands, Karolinska Institutet [Stockholm], Université de Sherbrooke (UdeS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), INSERM, INRA, Aix-Marseille Universite, Ministere de la Recherche et de l'Enseignement Superieur, Prostate Cancer Canada [D2013-8, 2012-951, TAG2014-02], Canadian Cancer Society Research Institute [701590], Fonds Wetenschappelijk Onderzoek (FWO) Vlaanderen, Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Sherbrooke [Sherbrooke]
Subjects: animal structures, MESH: Receptor, Insulin, Insulin-like Growth Factor (IGF), viruses, Insulin Receptor, education, Immunoblotting, MESH: Furin, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Real-Time Polymerase Chain Reaction, Mitogenic Signaling, MESH: Insulin-Like Growth Factor II, Mice, Cell Signaling, Insulin-Like Growth Factor II, health services administration, 3T3-L1 Cells, MESH: Cell Proliferation, Animals, Humans, Insulin, Furin, Metabolic Signaling, Proprotein Convertase, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Serine Endopeptidases, MESH: Mice, insuline, health care economics and organizations, Cell Proliferation, MESH: Humans, MESH: Immunoblotting, MESH: Real-Time Polymerase Chain Reaction, Serine Endopeptidases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Receptor, Insulin, humanities, MESH: 3T3-L1 Cells, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], HEK293 Cells, MESH: HEK293 Cells, MESH: HeLa Cells, MESH: Proprotein Convertases, Proprotein Convertases, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, HeLa Cells
Abstract: International audience; Background: The insulin receptor exists as two isoforms: IRA and IRB. Results: IRA and IRB are similarly matured by furin, but when furin activity is reduced, IRB is matured by PACE4. Conclusion: Proprotein convertase inhibition can selectively reduce IRA maturation and its signaling. Significance: This can be considered as a new opportunity to target IRA signaling in cancer. Gaining the full activity of the insulin receptor (IR) requires the proteolytic cleavage of its proform by intra-Golgi furin-like activity. In mammalian cells, IR is expressed as two isoforms (IRB and IRA) that are responsible for insulin action. However, only IRA transmits the growth-promoting and mitogenic effects of insulin-like growth factor 2. Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation. Therefore, in situations of impaired furin activity, the proteolytic maturation of IRB is greater than that of IRA, and accordingly, the amount of phosphorylated IRB is also greater than that of IRA. We highlight the ability of a particular proprotein convertase inhibitor to effectively reduce the maturation of IRA and its associated mitogenic signaling without altering the signals emanating from IRB. In conclusion, the selective PACE4-dependent maturation of IRB occurs when furin activity is reduced; accordingly, the pharmacological inhibition of furin reduces IRA maturation and its mitogenic potential without altering the insulin effects.
Published: 2015
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9. Cdk4 promotes adipogenesis through PPARγ activation

Author: Pierre Dubus, Françoise Vignon, Dominique Langin, Lluis Fajas, Anna Abella, Mariano Barbacid, Sushil G. Rane, Marcos Malumbres, Audrey Sicard, Hiroaki Kiyokawa, Endocrinologie moléculaire et cellulaire des cancers, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Histologie et Pathologie Moléculaire, Université Bordeaux Segalen - Bordeaux 2, Centro Nacional de Investigaciones Oncologicas Carlos III, Laboratory of cell regulation and carcinogenesis, Cell Cycle and Human Diseases Group, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, University of Illinois System-University of Illinois System, Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), This work was supported by grants of INSERM (Avenir), FRM, Alfediam, and ARC. Anna Abella is supported by a grant of Inserm Poste Vert. P. Dubus is supported by the Inserm (CreS 4CR03G)., Centro Nacional de Investigaciones Oncologicas / Spanish National Cancer Research Centre [Madrid, Espagne] (CNIO), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Le Ster, Yves
Subjects: endocrine system diseases, Physiology, MESH: Trans, Regulator, Mice, chemistry.chemical_compound, Genes, Reporter, Adipocyte, Adipocytes, E2F1, MESH: Animals, Cyclin, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Adipogenesis, integumentary system, Kinase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cell cycle, MESH: Gene Expression Regulation, Cell biology, MESH: Glucose, Protein Transport, biological phenomena, cell phenomena, and immunity, Protein Binding, MESH: Protein Transport, endocrine system, medicine.medical_specialty, MESH: Cyclin-Dependent Kinase 4, MESH: Biological Transport, Biology, Transfection, MESH: Mice, Inbred C57BL, 3T3-L1 Cells, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, MESH: Mice, Molecular Biology, MESH: Adipocytes, MESH: RNA, Messenger, MESH: Humans, MESH: Genes, Reporter, Cyclin-Dependent Kinase 4, Biological Transport, Cell Biology, Embryonic stem cell, MESH: 3T3-L1 Cells, Mice, Inbred C57BL, PPAR gamma, enzymes and coenzymes (carbohydrates), Glucose, Endocrinology, Gene Expression Regulation, MESH: PPAR gamma, chemistry, MESH: Adipogenesis
Abstract: SummaryCell cycle regulators such as E2F1 and retinoblastoma (RB) play crucial roles in the control of adipogenesis, mostly by controlling the transition between preadipocyte proliferation and adipocyte differentiation. The serine-threonine kinase cyclin-dependent kinase 4 (cdk4) works in a complex with D-type cyclins to phosphorylate RB, mediating the entry of cells into the cell cycle in response to external stimuli. Because cdk4 is an upstream regulator of the E2F-RB pathway, we tested whether cdk4 was a target for new factors that regulate adipogenesis. Here we find that cdk4 inhibition impairs adipocyte differentiation and function. Disruption of cdk4 or activating mutations in cdk4 in primary mouse embryonic fibroblasts results in reduced and increased adipogenic potential, respectively, of these cells. We show that the effects of cdk4 are not limited to the control of differentiation; cdk4 also participates in adipocyte function through activation of PPARγ.
Published: 2005
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10. Peroxisome proliferator-activated receptor γ regulates genes involved in insulin/insulin-like growth factor signaling and lipid metabolism during adipogenesis through functionally distinct enhancer classes

Author: Oger, Frederik, Dubois-Chevalier, Julie, Gheeraert, Celine, Avner, Stephane, Durand, Emmanuel, Froguel, Philippe, Salbert, Gilles, Staels, Bart, Lefebvre, Philippe, Eeckhoute, Jerome, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Derudas, Marie-Hélène
Subjects: Epigenomics, MESH: Signal Transduction, MESH: Insulin, chromatin modification, Transcrip tion regulation, MESH: Reverse Transcriptase Polymerase Chain Reaction, DNA methylat ion, MESH: Gene Expression Regulation, Developmental, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Protein Binding, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Somatomedins, MESH: Mice, insulin/insulin-like growth factor signalling, MESH: Adipocytes, MESH: Lipid Metabolism, MESH: Chromatin Immunoprecipitation, Adipogenesis, MESH: Muscle Fibers, Skeletal, MESH: Transcriptome, MESH: 3T3-L1 Cells, MESH: Cell Line, MESH: PPAR gamma, Peroxisome proliferator-activated receptor (PPAR), MESH: Enhancer Elements, Genetic, MESH: Adipogenesis, Transcription enhancers
Abstract: International audience; The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPAR induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPAR also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPAR utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process.
Published: 2014
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11. A New Pyrroline Compound Selective for I1-Imidazoline Receptors Improves Metabolic Syndrome in Rats

Author: Lyne Fellmann, Véronique Regnault, Nathalie Niederhoffer, Bruno Fève, Pascal Bousquet, A. Muscat, Vincent Gasparik, Anne Pizard, Jean-Pierre Max, Luc Gigou, Claude Julien, Hugues Greney, Patrick Lacolley, Gérard S. Chetrite, Valérie Oréa, Laboratoire de neurobiologie et pharmacologie cardiovasculaire (LNPCV), Université de Strasbourg (UNISTRA), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Pathologies biliaires, fibrose et cancer du foie, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon
Subjects: Male, Sympathetic nervous system, Sympathetic Nervous System, MESH: Rats, Inbred SHR, Adipose tissue, Blood Pressure, MESH: Rats, Sprague-Dawley, 030204 cardiovascular system & hematology, Kidney, Intestinal absorption, Rats, Sprague-Dawley, Mice, 0302 clinical medicine, Rats, Inbred SHR, Adiponectin secretion, MESH: Animals, MESH: Sympathetic Nervous System, Receptor, Metabolic Syndrome, 0303 health sciences, Glucose tolerance test, Aniline Compounds, medicine.diagnostic_test, Chemistry, MESH: Real-Time Polymerase Chain Reaction, MESH: Blood Pressure, MESH: Adiponectin, Lipids, 3. Good health, MESH: Surface Plasmon Resonance, MESH: Insulin Resistance, medicine.anatomical_structure, MESH: Pyrroles, Molecular Medicine, Adiponectin, MESH: Imidazoline Receptors, medicine.medical_specialty, MESH: Rats, MESH: Metabolic Syndrome, MESH: Glucose Tolerance Test, Real-Time Polymerase Chain Reaction, MESH: Aniline Compounds, 03 medical and health sciences, Insulin resistance, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3T3-L1 Cells, Internal medicine, Glucose Intolerance, medicine, Animals, Pyrroles, MESH: Mice, MESH: Glucose Intolerance, 030304 developmental biology, Pharmacology, Body Weight, MESH: Kidney, Glucose Tolerance Test, Surface Plasmon Resonance, medicine.disease, MESH: Lipids, MESH: 3T3-L1 Cells, MESH: Male, Rats, MESH: Body Weight, Endocrinology, Imidazoline Receptors, Insulin Resistance
Abstract: International audience; Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmacotherapy. LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride], a new pyrroline derivative, displaced the specific [(125)I]para-iodoclonidine binding to I1R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes. In addition, it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I1Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it increased plasma adiponectin. The pyrroline derivative, which inhibits sympathetic activity and stimulates adiponectin secretion, has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS.
Published: 2013
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12. Palmitoylation of TNF alpha is involved in the regulation of TNF receptor 1 signalling

Author: Marie-Christine Alessi, Jean Michel Brunel, Roland Govers, Bernadette Bonardo, Imène Kara, Regina Fluhrer, Jean-François Landrier, Christian Haass, Marjorie Poggi, Franck Peiretti, ProdInra, Migration, Nutriments Lipidiques et Prévention des Maladies Métaboliques, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de la Méditerranée - Aix-Marseille 2, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig-Maximilians University [Munich] (LMU), German Ctr Neurodegenerat Dis, Partenaires INRAE, INSERM, INRA, Aix-Marseille Universite, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université de la Méditerranée - Aix-Marseille 2, Ludwig Maximilians University of Munich, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: metabolism [Interleukin-6], medicine.medical_treatment, metabolism [Tumor Necrosis Factor-alpha], Fluorescent Antibody Technique, MESH: NF-kappa B, PROTEIN, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], metabolism [Membrane Microdomains], Immunoenzyme Techniques, Mice, 0302 clinical medicine, metabolism [Mitogen-Activated Protein Kinase 3], MESH: Animals, MESH: Fluorescent Antibody Technique, Cells, Cultured, Mitogen-Activated Protein Kinase 1, 0303 health sciences, Mitogen-Activated Protein Kinase 3, NF-kappa B, Transmembrane protein, Cell biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV] Life Sciences [q-bio], Ectodomain, metabolism [Luciferases], Receptors, Tumor Necrosis Factor, Type I, 030220 oncology & carcinogenesis, Tumor necrosis factor alpha, MESH: Mitogen-Activated Protein Kinase 3, MESH: Mitogen-Activated Protein Kinase 1, MESH: Cells, Cultured, MESH: Enzyme Activation, Lipoylation, Blotting, Western, 03 medical and health sciences, Enzyme activator, Humans, MESH: Blotting, Western, RNA, Messenger, MESH: Immunoenzyme Techniques, Molecular Biology, Lipid rafts, genetics [Membrane Microdomains], genetics [Tumor Necrosis Factor-alpha], MESH: Humans, MESH: Phosphorylation, Tumor Necrosis Factor-alpha, genetics [Caspase 8], Macrophages, PATHWAYS, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Interleukin-6, MESH: 3T3-L1 Cells, Enzyme Activation, TNFR1, MESH: Tumor Necrosis Factor-alpha, metabolism [Macrophages], MESH: Luciferases, INDUCED CELL-DEATH, genetics [NF-kappa B], HeLa Cells, MESH: Signal Transduction, [SDV]Life Sciences [q-bio], NF-KAPPA-B, MESH: Membrane Microdomains, TNF, MESH: Caspase 8, metabolism [Receptors, Tumor Necrosis Factor, Type I], ACTIVATION, INTRAMEMBRANE PROTEOLYSIS, genetics [Mitogen-Activated Protein Kinase 1], MESH: Reverse Transcriptase Polymerase Chain Reaction, Phosphorylation, Luciferases, Lipid raft, TUMOR-NECROSIS-FACTOR, MESH: Receptors, Tumor Necrosis Factor, Type I, Caspase 8, Reverse Transcriptase Polymerase Chain Reaction, MESH: Real-Time Polymerase Chain Reaction, MESH: Enzyme-Linked Immunosorbent Assay, respiratory system, MESH: Gene Expression Regulation, Cytokine, Biochemistry, metabolism [NF-kappa B], lipids (amino acids, peptides, and proteins), Signal transduction, metabolism [Caspase 8], Palmitoylation, Signal Transduction, EXPRESSION, MESH: Lipoylation, Enzyme-Linked Immunosorbent Assay, genetics [Interleukin-6], cytology [Macrophages], Signalling, Biology, Real-Time Polymerase Chain Reaction, TRANSDUCTION, genetics [RNA, Messenger], Membrane Microdomains, metabolism [Mitogen-Activated Protein Kinase 1], ddc:570, 3T3-L1 Cells, genetics [Mitogen-Activated Protein Kinase 3], medicine, Animals, Immunoprecipitation, ddc:610, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Interleukin-6, MESH: Immunoprecipitation, MESH: Macrophages, Cell Biology, Gene Expression Regulation, MESH: HeLa Cells, LIPRAFTS, genetics [Receptors, Tumor Necrosis Factor, Type I], [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: International audience; The pleiotropic pro-inflammatory cytokine tumour necrosis factor alpha (TNF) is synthesised as a transmembrane protein that is subject to palmitoylation. In this study, the roles of this acylation on TNF-mediated biological effects were investigated. We found that the lipid raft partitioning of TNF is regulated by its palmitoylation. Furthermore, we demonstrated that this palmitoylation process interferes with the cleavage/degradation of TNF intracellular fragments but is not involved in the regulation of its ectodomain shedding. Moreover, we found that the palmitoylation of TNF hinders the binding of soluble TNF to TNFR1 and regulates the integration/retention of TNFR1 into lipid rafts. Finally, we demonstrate that the transmembrane forms of wild-type and palmitoylation-defective TNF interact differently with TNFR1 and regulate NF kappa B activity, Erk1/2 phosphorylation and interleukin-6 synthesis differently, strongly suggesting that palmitoylation of TNF is involved in the regulation of TNFR1 signalling. An evidence for the physiological intervention of this regulation is provided by the fact that in macrophages, the binding of endogenous soluble TNF to TNFR1 is enhanced by inhibition of palmitoylation. Therefore, our data introduce the new concept that palmitoylation of TNF is one of the means by which TNF-producing cells regulate their sensitivity to soluble TNF. (C) 2012 Elsevier B.V. All rights reserved.
Published: 2013
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13. Deciphering the role of GLUT4 N-glycosylation in adipocyte and muscle cell models

Author: Roland Govers, Nancy Zaarour, Yannick Le Marchand-Brustel, Marion Berenguer, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Nice-Sophia-Antipolis, Conseil Régional Provence-Alpes-Côte d'Azur, Conseil Général des Alpes Maritimes, Alfediam-Roche Diagnostics award, Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre méditérannéen de médecine moléculaire ( C3M ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Nutrition, obésité et risque thrombotique ( NORT ), and Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Glycosylation, MESH : Mutant Proteins, endocrine system diseases, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, medicine.medical_treatment, MESH : Adipocytes, N-glycosylation, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, Myoblasts, Mice, chemistry.chemical_compound, MESH: Mutant Proteins, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Adipocyte, Adipocytes, MESH : Glucose Transporter Type 4, Myocyte, MESH: Animals, Internalization, MESH : Immunoblotting, media_common, 0303 health sciences, Glucose Transporter Type 4, biology, MESH: Immunoblotting, MESH : Glycosylation, 030302 biochemistry & molecular biology, musculoskeletal system, MESH: Glycosylation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: Glucose, glucose transporter 4 (GLUT4), MESH : 3T3-L1 Cells, MESH : Mutation, intracellular retention, Intracellular, hormones, hormone substitutes, and hormone antagonists, MESH : Proteolysis, MESH: Mutation, intracellular trafficking, MESH : Cell Membrane, media_common.quotation_subject, MESH: Biological Transport, Immunoblotting, MESH: Proteolysis, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, adipocyte, MESH : Myoblasts, 03 medical and health sciences, 3T3-L1 Cells, MESH : Mice, medicine, Animals, MESH: Myoblasts, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH : Glucose, Insulin, Cell Membrane, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Glucose transporter, nutritional and metabolic diseases, Biological Transport, Transporter, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: 3T3-L1 Cells, MESH : Biological Transport, Glucose, chemistry, Mutation, Proteolysis, biology.protein, Mutant Proteins, MESH : Animals, myoblast, MESH: Glucose Transporter Type 4, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, GLUT4, MESH: Cell Membrane
Abstract: International audience; GLUT4 (glucose transporter 4) is responsible for the insulin-induced uptake of glucose by muscle and fat cells. In non-stimulated (basal) cells, GLUT4 is retained intracellularly, whereas insulin stimulation leads to its translocation from storage compartments towards the cell surface. How GLUT4 is retained intracellularly is largely unknown. Previously, aberrant GLUT4 N-glycosylation has been linked to increased basal cell-surface levels, while N-glycosylation-deficient GLUT4 was found to be quickly degraded. As recycling and degradation of GLUT4 are positively correlated, we hypothesized that incorrect N-glycosylation of GLUT4 might reduce its intracellular retention, resulting in an increased cell-surface recycling, in increased basal cell-surface levels, and in enhanced GLUT4 degradation. In the present study, we have investigated N-glycosylation-deficient GLUT4 in detail in 3T3-L1 preadipocytes, 3T3-L1 adipocytes and L6 myoblasts. We have found no alterations in retention, insulin response, internalization or glucose transport activity. Degradation of the mutant molecule was increased, although once present at the cell surface, its degradation was identical with that of wild-type GLUT4. Our findings indicate that N-glycosylation is important for efficient trafficking of GLUT4 to its proper compartments, but once the transporter has arrived there, N-glycosylation plays no further major role in its intracellular trafficking, nor in its functional activity.
Published: 2012
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14. Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers

Author: Raphaël Métivier, Philippe Froguel, Gaëlle Palierne, Jérôme Eeckhoute, Frédérik Oger, Céline Lucchetti-Miganeh, Bart Staels, Emmanuelle Durand, Frédérique Barloy-Hubler, Aurélien A. Sérandour, Stéphane Avner, Frédéric Percevault, Maud Bizot, Thierry Madigou, Gilles Salbert, Philippe Lefebvre, Céline Gheeraert, Christine Le Péron, De Villemeur, Hervé, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The Ligue National Contre le Cancer [Equipe Labellisée Ligue 2009 to G.S.], the Agence Nationale pour la Recherche [ANR-09-BLAN-0268-01 to G.S.], the Région Bretagne [CREATE-DYNAMED-4793 to R.M. and SAD 08HC-315-02 to J.E.], F.O. and C.G. were supported by OSEO-ANVAR [IT-DIAB], A.A.S. was a recipient of a PhD fellowship from the Ministère de la Recherche. Funding for open access charge: CNRS., Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Subjects: MESH: Neoplasm Proteins, MESH: Cytosine, Cellular differentiation, Enhancer RNAs, Mice, 0302 clinical medicine, MESH: DNA Methylation, MESH: Animals, Myeloid Ecotropic Viral Integration Site 1 Protein, 0303 health sciences, Cell Differentiation, MESH: Transcription Factors, Chromatin, Cell biology, Neoplasm Proteins, DNA-Binding Proteins, P19 cell, Enhancer Elements, Genetic, DNA methylation, 5-Methylcytosine, DNA Hydroxymethylation, MESH: Cell Differentiation, MESH: Cell Line, Tumor, Neurogenesis, Biology, Gene Regulation, Chromatin and Epigenetics, MESH: Chromatin, 03 medical and health sciences, Cytosine, 3T3-L1 Cells, Cell Line, Tumor, Proto-Oncogene Proteins, MESH: Homeodomain Proteins, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Enhancer, Transcription factor, MESH: Mice, 030304 developmental biology, Homeodomain Proteins, Binding Sites, DNA Methylation, Molecular biology, MESH: 3T3-L1 Cells, MESH: Neurogenesis, MESH: Proto-Oncogene Proteins, MESH: Binding Sites, MESH: Enhancer Elements, Genetic, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Transcription Factors
Abstract: International audience; Enhancers are developmentally controlled transcriptional regulatory regions whose activities are modulated through histone modifications or histone variant deposition. In this study, we show by genome-wide mapping that the newly discovered deoxyribonucleic acid (DNA) modification 5-hydroxymethylcytosine (5hmC) is dynamically associated with transcription factor binding to distal regulatory sites during neural differentiation of mouse P19 cells and during adipocyte differentiation of mouse 3T3-L1 cells. Functional annotation reveals that regions gaining 5hmC are associated with genes expressed either in neural tissues when P19 cells undergo neural differentiation or in adipose tissue when 3T3-L1 cells undergo adipocyte differentiation. Furthermore, distal regions gaining 5hmC together with H3K4me2 and H3K27ac in P19 cells behave as differentiation-dependent transcriptional enhancers. Identified regions are enriched in motifs for transcription factors regulating specific cell fates such as Meis1 in P19 cells and PPARγ in 3T3-L1 cells. Accordingly, a fraction of hydroxymethylated Meis1 sites were associated with a dynamic engagement of the 5-methylcytosine hydroxylase Tet1. In addition, kinetic studies of cytosine hydroxymethylation of selected enhancers indicated that DNA hydroxymethylation is an early event of enhancer activation. Hence, acquisition of 5hmC in cell-specific distal regulatory regions may represent a major event of enhancer progression toward an active state and participate in selective activation of tissue-specific genes.
Published: 2012
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15. Dimethyl sulfoxide enhances GLUT4 translocation through a reduction in GLUT4 endocytosis in insulin-stimulated 3T3-L1 adipocytes

Author: Marion Berenguer, Andrey A. Gurtovenko, Jinzhong Zhang, Yannick Le Marchand-Brustel, Laurène Martinez, Roland Govers, Teresa Gonzalez, Tao Xu, M. Christine Bruce, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Northeastern University [Boston], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Rock Instability and Seismicity Research, Northeastern University [Shenyang], Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)
Subjects: endocrine system diseases, Glucose uptake, medicine.medical_treatment, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, Mice, 0302 clinical medicine, Adipocytes, Insulin, MESH: Animals, 0303 health sciences, MESH: Exocytosis, Glucose Transporter Type 4, biology, General Medicine, musculoskeletal system, Endocytosis, Cell biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: Glucose, Protein Transport, MESH: Endocytosis, MESH: Molecular Chaperones, hormones, hormone substitutes, and hormone antagonists, MESH: Protein Transport, MESH: Insulin, Exocytosis, 03 medical and health sciences, 3T3-L1 Cells, medicine, Animals, Dimethyl Sulfoxide, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Mice, MESH: Adipocytes, 030304 developmental biology, Glucose transporter, MESH: Dimethyl Sulfoxide, nutritional and metabolic diseases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: 3T3-L1 Cells, Insulin receptor, Glucose, biology.protein, GLUT1, MESH: Glucose Transporter Type 4, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, GLUT4, Molecular Chaperones
Abstract: International audience; Insulin increases muscle and fat cell glucose uptake by inducing the translocation of glucose transporter GLUT4 from intracellular compartments to the plasma membrane. Here, we have demonstrated that in 3T3-L1 adipocytes, DMSO at concentrations higher than 7.5% augmented cell surface GLUT4 levels in the absence and presence of insulin, but that at lower concentrations, DMSO only enhanced GLUT4 levels in insulin-stimulated cells. At a 5% concentration, DMSO also increased cell surface levels of the transferrin receptor and GLUT1. Glucose uptake experiments indicated that while DMSO enhanced cell surface glucose transporter levels, it also inhibited glucose transporter activity. Our studies further demonstrated that DMSO did not sensitize the adipocytes for insulin and that its effect on GLUT4 was readily reversible (t1/2∼12 min) and maintained in insulin-resistant adipocytes. An enhancement of insulin-induced GLUT4 translocation was not observed in 3T3-L1 preadipocytes and L6 myotubes, indicating cell specificity. DMSO did not enhance insulin signaling nor exocytosis of GLUT4 vesicles, but inhibited GLUT4 internalization. While other chemical chaperones (glycerol and 4-phenyl butyric acid) also acutely enhanced insulin-induced GLUT4 translocation, these effects were not mediated via changes in GLUT4 endocytosis. We conclude that DMSO is the first molecule to be described that instantaneously enhances insulin-induced increases in cell surface GLUT4 levels in adipocytes, at least in part through a reduction in GLUT4 endocytosis.
Published: 2011
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16. Cyclin G2 regulates adipogenesis through PPAR gamma coactivation

Author: Aguilar, Victor, Annicotte, Jean-Sébastien, Escote, Xavier, Vendrell, Joan, Langin, Dominique, Fajas, Lluis, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Endocrinology and Diabetes Unit, University Hospital of Tarragona, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from FRM, INCA, and ANR., and Le Ster, Yves
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, PPARγ, MESH: Immunoprecipitation, MESH: Transfection, MESH: Cyclin G2, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: 3T3-L1 Cells, MESH: Male, adipogenesis, MESH: PPAR gamma, MESH: Mice, Inbred C57BL, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Up-Regulation, cyclin G2, MESH: Animals, MESH: Adipogenesis, MESH: Fluorescent Antibody Technique, MESH: Mice, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Adipocytes, MESH: Cells, Cultured
Abstract: International audience; Cell cycle regulators such as cyclins, cyclin-dependent kinases, or retinoblastoma protein play important roles in the differentiation of adipocytes. In the present paper, we investigated the role of cyclin G2 as a positive regulator of adipogenesis. Cyclin G2 is an unconventional cyclin which expression is up-regulated during growth inhibition or apoptosis. Using the 3T3-F442A cell line, we observed an up-regulation of cyclin G2 expression at protein and mRNA levels throughout the process of cell differentiation, with a further induction of adipogenesis when the protein is transiently overexpressed. We show here that the positive regulatory effects of cyclin G2 in adipocyte differentiation are mediated by direct binding of cyclin G2 to peroxisome proliferator-activated receptor γ (PPARγ), the key regulator of adipocyte differentiation. The role of cyclin G2 as a novel PPARγ coactivator was further demonstrated by chromatin immunoprecipitation assays, which showed that the protein is present in the PPARγ-responsive element of the promoter of aP2, which is a PPARγ target gene. Luciferase reporter gene assays, showed that cyclin G2 positively regulates the transcriptional activity of PPARγ. The role of cyclin G2 in adipogenesis is further underscored by its increased expression in mice fed a high-fat diet. Taken together, our results demonstrate a novel role for cyclin G2 in the regulation of adipogenesis.
Published: 2010
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17. Proteasomal degradation of retinoid X receptor alpha reprograms transcriptional activity of PPARgamma in obese mice and humans

Author: François Pattou, Julie Dumont, Emmanuel Bouchaert, Alain Ktorza, Philippe Lefebvre, Catherine Dacquet, Aurore Guédin, Luc Pénicaud, Yacir Benomar, Audrey Langlois, Bruno Lefebvre, Louis Casteilla, Bart Staels, Nathalie Hennuyer, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Division of Meabolic Diseases, Institut de Recherches Servier, Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Thérapie cellulaire du diabète, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Division of Metabolic Diseases, Derudas, Marie-Hélène, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Transcription, Genetic, Peroxisome proliferator-activated receptor, Mice, Obese, White adipose tissue, MESH: Thiazolidinediones, MESH: Retinoid X Receptor alpha, Mice, 0302 clinical medicine, MESH: Obesity, MESH: Animals, MESH: Mice, Obese, chemistry.chemical_classification, 0303 health sciences, MESH: Proteasome Endopeptidase Complex, General Medicine, MESH: Gene Expression Regulation, MESH: Insulin Resistance, Adipose Tissue, Signal transduction, Ubiquitin Thiolesterase, MESH: Adipose Tissue, Research Article, Agonist, medicine.medical_specialty, Proteasome Endopeptidase Complex, medicine.drug_class, 030209 endocrinology & metabolism, Retinoid X receptor, Biology, Rosiglitazone, 03 medical and health sciences, Downregulation and upregulation, Internal medicine, 3T3-L1 Cells, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, MESH: Mice, 030304 developmental biology, Thyroid hormone receptor, Retinoid X Receptor alpha, MESH: Humans, Retinoid X receptor alpha, MESH: Transcription, Genetic, MESH: Ubiquitin Thiolesterase, MESH: 3T3-L1 Cells, MESH: Male, PPAR gamma, Endocrinology, chemistry, Gene Expression Regulation, MESH: PPAR gamma, Thiazolidinediones, Insulin Resistance
Abstract: International audience; Obese patients have chronic, low-grade inflammation that predisposes to type 2 diabetes and results, in part, from dysregulated visceral white adipose tissue (WAT) functions. The specific signaling pathways underlying WAT dysregulation, however, remain unclear. Here we report that the PPARgamma signaling pathway operates differently in the visceral WAT of lean and obese mice. PPARgamma in visceral, but not subcutaneous, WAT from obese mice displayed increased sensitivity to activation by its agonist rosiglitazone. This increased sensitivity correlated with increased expression of the gene encoding the ubiquitin hydrolase/ligase ubiquitin carboxyterminal esterase L1 (UCH-L1) and with increased degradation of the PPARgamma heterodimerization partner retinoid X receptor alpha (RXRalpha), but not RXRbeta, in visceral WAT from obese humans and mice. Interestingly, increased UCH-L1 expression and RXRalpha proteasomal degradation was induced in vitro by conditions mimicking hypoxia, a condition that occurs in obese visceral WAT. Finally, PPARgamma-RXRbeta heterodimers, but not PPARgamma-RXRalpha complexes, were able to efficiently dismiss the transcriptional corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) upon agonist binding. Increasing the RXRalpha/RXRbeta ratio resulted in increased PPARgamma responsiveness following agonist stimulation. Thus, the selective proteasomal degradation of RXRalpha initiated by UCH-L1 upregulation modulates the relative affinity of PPARgamma heterodimers for SMRT and their responsiveness to PPARgamma agonists, ultimately activating the PPARgamma-controlled gene network in visceral WAT of obese animals and humans.
Published: 2010
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18. GLUT4 molecules are recruited at random for insertion within the plasma membrane upon insulin stimulation

Author: Roland Govers, Yannick Le Marchand-Brustel, Marion Berenguer, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: endocrine system diseases, medicine.medical_treatment, Cell, Stimulation, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, MESH: Dose-Response Relationship, Drug, Mice, Structural Biology, Insulin, MESH: Animals, Bovine serum albumin, biology, musculoskeletal system, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Dose–response relationship, Protein Transport, Membrane, medicine.anatomical_structure, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, MESH: Protein Transport, Protein trafficking, Biophysics, MESH: Insulin, Internal medicine, 3T3-L1 Cells, MESH: Hypoglycemic Agents, Genetics, medicine, Animals, Hypoglycemic Agents, Glucose transporter type 4, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, MESH: Mice, Protein translocation, Dose-Response Relationship, Drug, Cell Membrane, Glucose transporter, nutritional and metabolic diseases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: 3T3-L1 Cells, Endocrinology, biology.protein, MESH: Glucose Transporter Type 4, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, GLUT4, Insulin-responsive glucose transporter, MESH: Cell Membrane
Abstract: International audience; Glucose transporter 4 (GLUT4) is efficiently retained intracellularly. Here, we investigated the insulin-induced reduction of retention. While increasing insulin concentrations led to gradual increases in both the amount of recycling GLUT4 molecules and cell surface GLUT4 levels, the kinetics of the increase in time was independent of insulin concentration. To determine whether there are GLUT4 subpools that have a distinct insulin sensitivity, adipocytes were consecutively stimulated twice with a low concentration of insulin while recycling GLUT4 molecules were continuously labeled. This revealed that not the same pool of GLUT4 molecules was mobilized twice and thus that upon insulin stimulation, GLUT4 is likely to be recruited at random for insertion within the plasma membrane.
Published: 2010

19. cyclin G2 and adipocyte differentiation

Author: Joan Vendrell, Xavier Escoté, Victor Aguilar, Jean-Sébastien Annicotte, Lluis Fajas, Dominique Langin, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Endocrinology and Diabetes Unit, University Hospital of Tarragona, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), and This work was supported by grants from FRM, INCA, and ANR.
Subjects: Male, PPARγ, Cyclin D, Cyclin A, Cyclin B, Fluorescent Antibody Technique, Cultured Cyclin G2/genetics/*metabolism Fluorescent Antibody Technique Immunoprecipitation Male Mice Mice, Mice, Endocrinology, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Up-Regulation, Adipocytes, MESH: Animals, MESH: Fluorescent Antibody Technique, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cyclin, 0303 health sciences, Adipogenesis, biology, Reverse Transcriptase Polymerase Chain Reaction, 030302 biochemistry & molecular biology, MESH: Cyclin G2, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Up-Regulation, Cell biology, MESH: Cells, Cultured, 3T3-L1 Cells Adipocytes/cytology/*metabolism Adipogenesis/*genetics Animals Cells, Cyclin G2, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Transfection, Article, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Cyclin-dependent kinase, 3T3-L1 Cells, Animals, Immunoprecipitation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: Immunoprecipitation, MESH: Transfection, Inbred C57BL PPAR gamma/genetics/*metabolism Reverse Transcriptase Polymerase Chain Reaction Transfection Up-Regulation, MESH: 3T3-L1 Cells, MESH: Male, Mice, Inbred C57BL, PPAR gamma, MESH: PPAR gamma, biology.protein, Cyclin-dependent kinase complex, MESH: Adipogenesis, Cyclin A2
Abstract: International audience; Cell cycle regulators such as cyclins, cyclin-dependent kinases, or retinoblastoma protein play important roles in the differentiation of adipocytes. In the present paper, we investigated the role of cyclin G2 as a positive regulator of adipogenesis. Cyclin G2 is an unconventional cyclin which expression is up-regulated during growth inhibition or apoptosis. Using the 3T3-F442A cell line, we observed an up-regulation of cyclin G2 expression at protein and mRNA levels throughout the process of cell differentiation, with a further induction of adipogenesis when the protein is transiently overexpressed. We show here that the positive regulatory effects of cyclin G2 in adipocyte differentiation are mediated by direct binding of cyclin G2 to peroxisome proliferator-activated receptor γ (PPARγ), the key regulator of adipocyte differentiation. The role of cyclin G2 as a novel PPARγ coactivator was further demonstrated by chromatin immunoprecipitation assays, which showed that the protein is present in the PPARγ-responsive element of the promoter of aP2, which is a PPARγ target gene. Luciferase reporter gene assays, showed that cyclin G2 positively regulates the transcriptional activity of PPARγ. The role of cyclin G2 in adipogenesis is further underscored by its increased expression in mice fed a high-fat diet. Taken together, our results demonstrate a novel role for cyclin G2 in the regulation of adipogenesis.
Published: 2010
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20. A serum factor induces insulin-independent translocation of GLUT4 to the cell surface which is maintained in insulin resistance

Author: Marion Berenguer, Sophie Giorgetti-Peraldi, Roland Govers, Laurène Martinez, Yannick Le Marchand-Brustel, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Centre méditérannéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et pathologies (IFR50), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)
Subjects: MESH: Hepatocyte Growth Factor, medicine.medical_treatment, Glucose uptake, MESH: Insulin-Like Growth Factor I, lcsh:Medicine, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, Transmembrane Transport Proteins, Myoblasts, Mice, Endocrinology, 0302 clinical medicine, Insulin receptor substrate, Molecular Cell Biology, Adipocytes, Signaling in Cellular Processes, Insulin, MESH: Animals, Insulin-Like Growth Factor I, lcsh:Science, Platelet-Derived Growth Factor, 0303 health sciences, Glucose Transporter Type 4, Multidisciplinary, Hepatocyte Growth Factor, MESH: Platelet-Derived Growth Factor, musculoskeletal system, MESH: Gene Expression Regulation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Insulin oscillation, Insulin signaling, MESH: Glucose, Protein Transport, MESH: Insulin Resistance, Blood Chemistry, Medicine, Membranes and Sorting, hormones, hormone substitutes, and hormone antagonists, Research Article, Signal Transduction, medicine.medical_specialty, MESH: Protein Transport, MESH: Insulin, Biology, 03 medical and health sciences, Insulin resistance, 3T3-L1 Cells, Internal medicine, Receptors, Transferrin, medicine, Animals, Humans, MESH: Receptors, Transferrin, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Mice, Glucose signaling, MESH: Adipocytes, 030304 developmental biology, Diabetic Endocrinology, Plasma Proteins, MESH: Humans, lcsh:R, Glucose transporter, Proteins, Biological Transport, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Diabetes Mellitus Type 2, medicine.disease, Hormones, MESH: 3T3-L1 Cells, Transmembrane Proteins, Cell membranes, Insulin receptor, Metabolism, Glucose, Gene Expression Regulation, biology.protein, lcsh:Q, MESH: Glucose Transporter Type 4, 030217 neurology & neurosurgery, GLUT4
Abstract: International audience; In response to insulin, glucose transporter GLUT4 translocates from intracellular compartments towards the plasma membrane where it enhances cellular glucose uptake. Here, we show that sera from various species contain a factor that dose-dependently induces GLUT4 translocation and glucose uptake in 3T3-L1 adipocytes, human adipocytes, myoblasts and myotubes. Notably, the effect of this factor on GLUT4 is fully maintained in insulin-resistant cells. Our studies demonstrate that the serum-induced increase in cell surface GLUT4 levels is not due to inhibition of its internalization and is not mediated by insulin, PDGF, IGF-1, or HGF. Similarly to insulin, serum also augments cell surface levels of GLUT1 and TfR. Remarkably, the acute effect of serum on GLUT4 is largely additive to that of insulin, while it also sensitizes the cells to insulin. In accordance with these findings, serum does not appear to activate the same repertoire of downstream signaling molecules that are implicated in insulin-induced GLUT4 translocation. We conclude that in addition to insulin, at least one other biological proteinaceous factor exists that contributes to GLUT4 regulation and still functions in insulin resistance. The challenge now is to identify this factor.
Published: 2010
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21. Hypoxia decreases insulin signaling pathways in adipocytes

Author: Issam Ben-Sahra, Yannick Le Marchand-Brustel, Frédéric Bost, T Grémeaux, Sophie Giorgetti-Peraldi, Mireille Cormont, Claire Regazzetti, Jean-François Tanti, Rosanna Najem-Lendom, Pascal Peraldi, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Signalisation moléculaire et obésité, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditérannéen de médecine moléculaire (C3M), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Signal Transduction, medicine.medical_specialty, MESH: Receptor, Insulin, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, MESH: Biological Transport, MESH: Cell Hypoxia, Adipose tissue, 030209 endocrinology & metabolism, MESH: Insulin, MESH: Protein Tyrosine Phosphatases, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Downregulation and upregulation, MESH: Glycerol, MESH: Interleukin-1beta, Insulin receptor substrate, Internal medicine, MESH: Hypoglycemic Agents, MESH: Basic Helix-Loop-Helix Transcription Factors, Internal Medicine, medicine, MESH: Blotting, Western, MESH: Lipolysis, MESH: Animals, Protein kinase B, MESH: Mice, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Adipocytes, 030304 developmental biology, 0303 health sciences, MESH: Humans, biology, MESH: Phosphorylation, Insulin, MESH: Reactive Oxygen Species, medicine.disease, MESH: Interleukin-6, MESH: 3T3-L1 Cells, MESH: Cell Line, MESH: Glucose, Insulin receptor, MESH: Cobalt, Endocrinology, biology.protein, Phosphorylation
Abstract: OBJECTIVE—Obesity is characterized by an overgrowth of adipose tissue that leads to the formation of hypoxic areas within this tissue. We investigated whether this phenomenon could be responsible for insulin resistance by studying the effect of hypoxia on the insulin signaling pathway in adipocytes. RESEARCH DESIGN AND METHODS—The hypoxic signaling pathway was modulated in adipocytes from human and murine origins through incubation under hypoxic conditions (1% O2) or modulation of hypoxia-inducible factor (HIF) expression. Insulin signaling was monitored through the phosphorylation state of several key partners of the pathway and glucose transport. RESULTS—In both human and murine adipocytes, hypoxia inhibits insulin signaling as revealed by a decrease in the phosphorylation of insulin receptor. In 3T3-L1 adipocytes, this inhibition of insulin receptor phosphorylation is followed by a decrease in the phosphorylation state of protein kinase B and AS160, as well as an inhibition of glucose transport in response to insulin. These processes were reversible under normoxic conditions. The mechanism of inhibition seems independent of protein tyrosine phosphatase activities. Overexpression of HIF-1α or -2α or activation of HIF transcription factor with CoCl2 mimicked the effect of hypoxia on insulin signaling, whereas downregulation of HIF-1α and -2α by small interfering RNA inhibited it. CONCLUSIONS—We have demonstrated that hypoxia creates a state of insulin resistance in adipocytes that is dependent upon HIF transcription factor expression. Hypoxia could be envisioned as a new mechanism that participates in insulin resistance in adipose tissue of obese patients.
Published: 2009
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22. Matrix metalloproteinase-11/stromelysin-3 exhibits collagenolytic function against collagen VI under normal and malignant conditions

Author: Nadia Messaddeq, Elena Roza Motrescu, Marlène Rio, M. P. Chenard, Isabelle Stoll, Nicolas Etique, Sébastien Blaise, Catherine Tomasetto, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Maquart, François-Xavier, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie Pathologique Générale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Extracellular Matrix Proteins, Cancer Research, MESH: Osteosarcoma, Extracellular matrix component, Matrix metalloproteinase, MESH: Silver Staining, Collagen receptor, MESH: Recombinant Proteins, chemistry.chemical_compound, Mice, 0302 clinical medicine, Collagen VI, MESH: Matrix Metalloproteinase 11, Adipocyte, MESH: Collagen, Adipocytes, Insulin, MESH: Animals, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, 0303 health sciences, Extracellular Matrix Proteins, Osteosarcoma, MESH: Glioblastoma, Cell Differentiation, Recombinant Proteins, Cell biology, Extracellular Matrix, Adipogenesis, 030220 oncology & carcinogenesis, Collagen, MESH: Cells, Cultured, MESH: Cell Differentiation, medicine.medical_specialty, Silver Staining, MESH: Cell Line, Tumor, MESH: Collagen Type VI, Collagen Type VI, MESH: Insulin, Biology, MESH: Extracellular Matrix, 03 medical and health sciences, Matrix Metalloproteinase 11, Internal medicine, 3T3-L1 Cells, Cell Line, Tumor, MESH: Hypoglycemic Agents, Genetics, medicine, Extracellular, Animals, Humans, Hypoglycemic Agents, Molecular Biology, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: Humans, MESH: Embryo, Mammalian, Fibroblasts, Embryo, Mammalian, [SDV.ETH] Life Sciences [q-bio]/Ethics, MESH: 3T3-L1 Cells, [SDV.ETH]Life Sciences [q-bio]/Ethics, Collagen, type I, alpha 1, Endocrinology, chemistry, MESH: Fibroblasts, Glioblastoma
Abstract: International audience; The substrate of matrix metalloproteinase 11 (MMP11) remains unknown. We have recently shown that MMP11 is a negative regulator of adipogenesis, able to reduce and even to revert mature adipocyte differentiation. Here, we have used mouse 3T3L1 cells and human U87MG and SaOS cells to show that MMP11 cleaves the native alpha3 chain of collagen VI, which is an adipocyte-related extracellular matrix component. It is known that extracellular proteolytic processing of this chain is required for correct collagen VI folding. Interestingly, MMP11-deficient fat tissue is less cohesive and exhibits collagen VI alteration, dramatic adipocyte plasma and basement membrane abnormalities and lipid leakage. MMP11 is thus required for correct collagen VI folding and therefore for fat tissue cohesion and adipocyte function. Both MMP11 and collagen VI favor tumor progression. Similar spatio-temporal overexpression at the adipocyte-cancer cell interface has been reported for the two proteins. MMP11-dependent collagen VI processing might therefore be expected to occur during malignancy. Accordingly, collagen VI no longer delineates adipocytes located at the invasive front of breast carcinomas. In conclusion, the native alpha3 chain of collagen VI constitutes a specific MMP11 substrate. This MMP11 collagenolytic activity is functional in fat tissue ontogenesis as well as during cancer invasive steps.
Published: 2008
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23. Evidence for an important role of CIDEA in human cancer cachexia

Author: Britta M Stenson, Elisabet Arvidsson Nordström, Jurga Laurencikiene, Peter Arner, Johan Permert, Thorhallur Agustsson, Mikael Rydén, Dominique Langin, Bengt Isaksson, Simon, Marie Francoise, Departments of Medicine, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Departments of Surgery, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Male, Cancer Research, Cachexia, White adipose tissue, Body Mass Index, chemistry.chemical_compound, Mice, Adipocyte, Neoplasms, Adipocytes, MESH: Neoplasms, MESH: Animals, Phosphorylation, PRDM16, MESH: Aged, MESH: Middle Aged, Fatty Acids, MESH: Energy Metabolism, Middle Aged, Pyruvate dehydrogenase complex, MESH: Fatty Acids, MESH: Glucose, Oncology, MESH: Adipose Tissue, White, Female, Adult, medicine.medical_specialty, Pyruvate dehydrogenase kinase, Adipose Tissue, White, PDK4, Pyruvate Dehydrogenase Complex, Biology, Protein Serine-Threonine Kinases, MESH: Protein-Serine-Threonine Kinases, MESH: Body Mass Index, MESH: Pyruvate Dehydrogenase Complex, Internal medicine, 3T3-L1 Cells, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Lipolysis, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, MESH: Mice, MESH: Adipocytes, Aged, MESH: RNA, Messenger, MESH: Humans, MESH: Phosphorylation, MESH: Apoptosis Regulatory Proteins, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, MESH: Adult, medicine.disease, MESH: 3T3-L1 Cells, MESH: Male, Endocrinology, Glucose, chemistry, MESH: Cachexia, Apoptosis Regulatory Proteins, Energy Metabolism, MESH: Female
Abstract: Loss of fat mass in cancer cachexia is linked to increased adipocyte lipolysis; however, the fate of the excess fatty acids (FA) generated by lipolysis is not known. We investigated if the adipocyte-specific gene cell death–inducing DNA fragmentation factor-α–like effector A (CIDEA) could be involved. CIDEA mRNA expression was assessed in s.c. white adipose tissue from 23 cancer cachexia patients, 17 weight-stable cancer patients, and 8 noncancer patients. CIDEA was also overexpressed in adipocytes in vitro. CIDEA expression was increased in cancer cachexia (P < 0.05) and correlated with elevated levels of FAs and reported weight loss (P < 0.001). CIDEA overexpression in vitro increased FA oxidation 2- to 4-fold (P < 0.01), decreased glucose oxidation by 40% (P < 0.01), increased the expression of pyruvate dehydrogenase kinase (PDK) 1 and PDK4 (P < 0.01), and enhanced the phosphorylation (inactivation) of the pyruvate dehydrogenase complex (PDC). Inactivation of PDC facilitates FA oxidation by favoring the metabolism of FAs over glucose to acetyl-CoA. In accordance with the in vitro data, PDK1 and PDK4 expression correlated strongly with CIDEA expression in white adipose tissue (P < 0.001). We conclude that CIDEA is involved in adipose tissue loss in cancer cachexia and this may, at least in part, be due to its ability to inactivate PDC, thereby switching substrate oxidation in human fat cells from glucose to FAs. [Cancer Res 2008;68(22):9247–54]
Published: 2008
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24. Adipogenesis-related increase of semicarbazide-sensitive amine oxidase and monoamine oxidase in human adipocytes

Author: Sandy Bour, Philippe Valet, Christian Carpéné, Sandra Grès, Jean-Sébastien Saulnier-Blache, Antonio Zorzano, Martin Wabitsch, Danièle Daviaud, Corinne Lefort, D. Prévot, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Departamento de Bioquimica y Biologia Molecular, Universidad de Barcelona, Department of Pediatrics and Adolescent Medicine, Universität Ulm - Ulm University [Ulm, Allemagne], Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: AOC3, MESH: 3T3 Cells, Adipose tissue, Biochemistry, Mice, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Adipocytes, MESH: Animals, 0303 health sciences, Adipogenesis, MESH: Middle Aged, Cell Differentiation, 3T3 Cells, General Medicine, Middle Aged, MESH: Infant, medicine.anatomical_structure, Female, Amine Oxidase (Copper-Containing), Adult, MESH: Cell Differentiation, medicine.medical_specialty, Amine oxidase, Monoamine oxidase, Biology, MESH: Monoamine Oxidase, 3T3 cells, 03 medical and health sciences, 3T3-L1 Cells, Internal medicine, medicine, Animals, Humans, Cell Lineage, RNA, Messenger, Monoamine Oxidase, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Infant, MESH: Adult, MESH: Cell Lineage, MESH: 3T3-L1 Cells, Endocrinology, chemistry, MESH: Amine Oxidase (Copper-Containing), MESH: Adipogenesis, MESH: Female, 030217 neurology & neurosurgery, Ex vivo
Abstract: International audience; A strong induction of semicarbazide-sensitive amine oxidase (SSAO) has previously been reported during murine preadipocyte lineage differentiation but it remains unknown whether this emergence also occurs during adipogenesis in man. Our aim was to compare SSAO and monoamine oxidase (MAO) expression during in vitro differentiation of human preadipocytes and in adipose and stroma-vascular fractions of human fat depots. A human preadipocyte cell strain from a patient with Simpson-Golabi-Behmel syndrome was first used to follow amine oxidase expression during in vitro differentiation. Then, human preadipocytes isolated from subcutaneous adipose tissues were cultured under conditions promoting ex vivo adipose differentiation and tested for MAO and SSAO expression. Lastly, human adipose tissue was separated into mature adipocyte and stroma-vascular fractions for analyses of MAO and SSAO at mRNA, protein and activity levels. Both SSAO and MAO were increased from undifferentiated preadipocytes to lipid-laden cells in all the models: 3T3-F442A and 3T3-L1 murine lineages, human SGBS cell strain or human preadipocytes in primary culture. In human subcutaneous adipose tissue, the adipocyte-enriched fraction exhibited seven-fold higher amine oxidase activity and contained three- to seven-fold higher levels of mRNAs encoded by MAO-A, MAO-B, AOC3 and AOC2 genes than the stroma-vascular fraction. MAO-A and AOC3 genes accounted for the majority of their respective MAO and SSAO activities in human adipose tissue. Most of the SSAO and MAO found in adipose tissue originated from mature adipocytes. Although the mechanism and role of adipogenesis-related increase in amine oxidase expression remain to be established, the resulting elevated levels of amine oxidase activities found in human adipocytes may be of potential interest for therapeutic intervention in obesity.
Published: 2007
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25. The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis

Author: Jerome N. Feige, Béatrice Desvergne, Daniel Rossi, Silvia I. Anghel, Laurent Gelman, Raphaël Métivier, Walter Wahli, Yves Engelborghs, Olivier Michielin, Vincent Zoete, Cicerone Tudor, Caroline Lathion, Aurélien Grosdidier, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), département de chimie, Université Catholique de Louvain = Catholic University of Louvain (UCL), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Fluorescence Resonance Energy Transfer, Peroxisome proliferator-activated receptor, 010501 environmental sciences, MESH: Thiazolidinediones, 01 natural sciences, Biochemistry, Mice, MESH: Protein Structure, Tertiary, Chlorocebus aethiops, MESH: RNA, Small Interfering, Adipocytes, Fluorescence Resonance Energy Transfer, MESH: Animals, RNA, Small Interfering, Receptor, Promoter Regions, Genetic, chemistry.chemical_classification, 0303 health sciences, Adipogenesis, 3. Good health, Cell biology, MESH: COS Cells, MESH: Promoter Regions (Genetics), Endocrine disruptor, MESH: Environmental Pollutants, COS Cells, Environmental Pollutants, Rosiglitazone, medicine.drug, medicine.medical_specialty, Context (language use), [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Internal medicine, 3T3-L1 Cells, Diethylhexyl Phthalate, MESH: Hypoglycemic Agents, MESH: Diethylhexyl Phthalate, medicine, Animals, Humans, Hypoglycemic Agents, Molecular Biology, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, 0105 earth and related environmental sciences, Binding Sites, MESH: Humans, Cell Biology, MESH: Cercopithecus aethiops, MESH: 3T3-L1 Cells, Protein Structure, Tertiary, PPAR gamma, MESH: Hela Cells, Endocrinology, chemistry, MESH: PPAR gamma, MESH: Binding Sites, Thiazolidinediones, Chromatin immunoprecipitation, MESH: Adipogenesis, Obesogen, HeLa Cells
Abstract: Jérôme N. Feige, Laurent Gelman (Both authors contributed equally to the reported work); International audience; The ability of pollutants to affect human health is a major concern, justified by the wide demonstration that reproductive functions are altered by endocrine disrupting chemicals. The definition of endocrine disruption is today extended to broader endocrine regulations, and includes activation of metabolic sensors, such as the peroxisome proliferator-activated receptors (PPARs). Toxicology approaches have demonstrated that phthalate plasticizers can directly influence PPAR activity. What is now missing is a detailed molecular understanding of the fundamental basis of endocrine disrupting chemical interference with PPAR signaling. We thus performed structural and functional analyses that demonstrate how monoethyl-hexyl-phthalate (MEHP) directly activates PPARgamma and promotes adipogenesis, albeit to a lower extent than the full agonist rosiglitazone. Importantly, we demonstrate that MEHP induces a selective activation of different PPARgamma target genes. Chromatin immunoprecipitation and fluorescence microscopy in living cells reveal that this selective activity correlates with the recruitment of a specific subset of PPARgamma coregulators that includes Med1 and PGC-1alpha, but not p300 and SRC-1. These results highlight some key mechanisms in metabolic disruption but are also instrumental in the context of selective PPAR modulation, a promising field for new therapeutic development based on PPAR modulation.
Published: 2007
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26. In vivo evidence for a role of adipose tissue SR-BI in the nutritional and hormonal regulation of adiposity and cholesterol homeostasis

Author: Georges Dagher, Alexandre Bobard, Florence Massiera, Laurent Yvan-Charvet, Xavier Rousset, Pascal Ferré, Michèle Teboul, Gérard Ailhaud, Pascale Bossard, Annie Quignard-Boulangé, Pathologies nutritionnelles et métaboliques : obésité et diabète, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Metabolisme et Differenciation Intestinale, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
Subjects: Male, Time Factors, Transcription, Genetic, medicine.medical_treatment, Angiotensinogen, Adipose tissue, Receptors, Cytoplasmic and Nuclear, White adipose tissue, 030204 cardiovascular system & hematology, MESH: Eating, Eating, Mice, 0302 clinical medicine, MESH: Cholesterol, Adipocytes, Homeostasis, Insulin, MESH: Animals, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Adiposity, Liver X Receptors, Epididymis, 0303 health sciences, Angiotensin II, Scavenger Receptors, Class B, Orphan Nuclear Receptors, DNA-Binding Proteins, Protein Transport, Cholesterol, Adipose Tissue, MESH: Homeostasis, Lipogenesis, MESH: ATP-Binding Cassette Transporters, lipids (amino acids, peptides, and proteins), MESH: Angiotensin II, MESH: Cholesterol, HDL, Cardiology and Cardiovascular Medicine, Sterol Regulatory Element Binding Protein 1, MESH: Adipose Tissue, ATP Binding Cassette Transporter 1, MESH: Triglycerides, medicine.medical_specialty, MESH: Protein Transport, MESH: Mice, Transgenic, Adipose tissue macrophages, MESH: Epididymis, MESH: Angiotensinogen, Mice, Transgenic, MESH: Insulin, Biology, MESH: Receptors, Cytoplasmic and Nuclear, 03 medical and health sciences, MESH: Sterol Regulatory Element Binding Protein 1, Internal medicine, 3T3-L1 Cells, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Liver X receptor, MESH: Mice, Triglycerides, MESH: Adipocytes, 030304 developmental biology, MESH: RNA, Messenger, MESH: Adiposity, MESH: Lipogenesis, MESH: Transcription, Genetic, Cell Membrane, Cholesterol, HDL, MESH: Time Factors, MESH: 3T3-L1 Cells, MESH: Male, MESH: Scavenger Receptors, Class B, Endocrinology, ATP-Binding Cassette Transporters, MESH: DNA-Binding Proteins, Lipoprotein, MESH: Cell Membrane
Abstract: Objectives— This study examines the role of insulin and angiotensin II in high-density lipoprotein (HDL) metabolism by focusing on the regulation and function of scavenger receptor type-BI (SR-BI) in adipose tissue. Methods and Results— Insulin or angiotensin II injection in wild-type mice induced a decrease in circulating HDL and it was associated with the translocation of SR-BI from intracellular sites to the plasma membrane of adipose tissue. Refeeding upregulated adipose HDL selective cholesteryl esters uptake and SR-BI proteins through transcriptional and posttranscriptional mechanisms. This occurred along with a decrease in serum HDL and an increase in adipose cholesterol content. Similar results were obtained with transgenic mice overexpressing locally angiotensinogen in adipose tissue. In adipose 3T3-L1 cell line, HDL induced lipogenesis by increasing liver X receptor binding activity. This mechanism was dependent of insulin and angiotensin II. Conclusions— Our results raise the possibility that adipose tissue SR-BI translocation might be a link between adipose tissue lipid storage and HDL clearance.
Published: 2007
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27. Inhibition of the anti-adipogenic Hedgehog signaling pathway by cyclopamine does not trigger adipocyte differentiation

Author: Wendy Cousin, Pascal Peraldi, Christian Dani, Peraldi, Pascal, Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
Subjects: MESH: Signal Transduction, Time Factors, Lipodystrophy, Cellular differentiation, MESH: Veratrum Alkaloids, Biochemistry, Dexamethasone, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Lipodystrophy, Adipocyte, 1-Methyl-3-isobutylxanthine, Adipocytes, Insulin, MESH: Animals, Oncogene Proteins, 0303 health sciences, biology, MESH: 1-Methyl-3-isobutylxanthine, Veratrum Alkaloids, Cell Differentiation, Hedgehog signaling pathway, Cell biology, Adipogenesis, 030220 oncology & carcinogenesis, MESH: Dexamethasone, Signal Transduction, MESH: Cell Differentiation, medicine.medical_specialty, Indian hedgehog, Cyclopamine, MESH: Trans-Activators, Biophysics, MESH: Insulin, Zinc Finger Protein GLI1, 03 medical and health sciences, MESH: Oncogene Proteins, GLI1, Internal medicine, 3T3-L1 Cells, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Hedgehog Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Hedgehog, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: Time Factors, Cell Biology, MESH: Hedgehog Proteins, biology.organism_classification, MESH: 3T3-L1 Cells, Endocrinology, chemistry, biology.protein, Trans-Activators
Abstract: International audience; Dysregulation of Hedgehog signaling can lead to several pathologies such as congenital defects and cancer. Here, we show that Hedgehog signaling is active in undifferentiated 3T3-L1 cells and decreases during adipocyte differentiation. Interestingly, this is paralleled by a decrease in Indian Hedgehog expression. We then tested if this down-regulation was sufficient to induce adipocyte differentiation. To this end, we demonstrate that the well-characterized Hedgehog inhibitor cyclopamine induced a decrease in Hedgehog signaling, similar to the one observed during adipocyte differentiation. However, cyclopamine did not induce nor potentiate adipocyte differentiation, as monitored by triglyceride staining and by the expression of several adipocyte markers: aP2, adipsin, C/EBPalpha, and Pref-1. Moreover, cyclopamine cannot substitute for other components of the differentiation medium: insulin, dexamethasone or IBMX. These results indicate that although Hedgehog signaling decreases during adipocyte differentiation, this down-regulation is not sufficient to trigger adipocyte differentiation. This suggests that Hedgehog signaling is an inadequate pharmacological target for patient suffering from syndromes associated with a decrease in fat mass, such as the ones observed in lipodystrophies.
Published: 2006
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28. Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma

Author: Béatrice Desvergne, Laurent Dubuquoy, Johan Auwerx, Philippe Lefebvre, Antoine Cortot, Amaury Farce, Daniel Metzger, Pierre Desreumaux, Bruno Lefebvre, Christel Rousseaux, Jean-Frederic Colombel, Gian Carlo Naccari, Olivier Romano, Philippe Chavatte, Philippe Bulois, Walter Wahli, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: HT29 Cells, Anti-Inflammatory Agents, Peroxisome proliferator-activated receptor, Pharmacology, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Colitis, Immunology and Allergy, MESH: Animals, Mesalamine, Regulation of gene expression, chemistry.chemical_classification, 0303 health sciences, Peroxisome, Colitis, MESH: Gene Expression Regulation, 3. Good health, 030211 gastroenterology & hepatology, Peroxisome proliferator-activated receptor alpha, HT29 Cells, medicine.medical_specialty, Peroxisome proliferator-activated receptor gamma, Aminosalicylic acid, Colon, Immunology, 3T3-L1 Cells, Animals, Gene Expression Regulation, Humans, Mice, Inbred Strains, PPAR gamma, RNA, Messenger, Biology, MESH: Mice, Inbred Strains, Article, 03 medical and health sciences, Internal medicine, medicine, MESH: Colon, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Mesalamine, medicine.disease, digestive system diseases, MESH: 3T3-L1 Cells, MESH: Male, Endocrinology, chemistry, Nuclear receptor, MESH: PPAR gamma, MESH: Anti-Inflammatory Agents
Abstract: International audience; 5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-gamma(+/-) mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-gamma expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element-driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-gamma as a target of 5-ASA underlying antiinflammatory effects in the colon.
Published: 2005
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29. Insulin stimulates the entry of GLUT4 into the endosomal recycling pathway by a quantal mechanism

Author: Coster, Adelle C F, Govers, Roland, James, David E, Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Govers, Roland
Subjects: MESH: Protein Transport, Time Factors, Monosaccharide Transport Proteins, endocrine system diseases, Muscle Proteins, Endosomes, MESH: Insulin, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Models, Biological, Exocytosis, MESH: Dose-Response Relationship, Drug, Mice, MESH: Muscle Proteins, 3T3-L1 Cells, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Insulin, MESH: Fluorescent Antibody Technique, Indirect, MESH: Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Fluorescent Antibody Technique, Indirect, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Mice, MESH: Exocytosis, Glucose Transporter Type 4, Dose-Response Relationship, Drug, MESH: Kinetics, Cell Membrane, MESH: Time Factors, MESH: Models, Biological, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, musculoskeletal system, MESH: 3T3-L1 Cells, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Kinetics, Protein Transport, MESH: Endosomes, MESH: Monosaccharide Transport Proteins, MESH: Glucose Transporter Type 4, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, hormones, hormone substitutes, and hormone antagonists, MESH: Cell Membrane
Abstract: International audience; The insulin-sensitive glucose transporter GLUT4 mediates the uptake of glucose into adipocytes and muscle cells. In this study we have used a novel 96-well plate fluorescence assay to study the kinetics of GLUT4 trafficking in 3T3-L1 adipocytes. We have found evidence for a graded release mechanism whereby GLUT4 is released into the plasma membrane recycling system in a nonkinetic manner as follows: the kinetics of appearance of GLUT4 at the plasma membrane is independent of the insulin concentration; a large proportion of GLUT4 molecules do not participate in plasma membrane recycling in the absence of insulin; and with increasing insulin there is an incremental increase in the total number of GLUT4 molecules participating in the recycling pathway rather than simply an increased rate of recycling. We propose a model whereby GLUT4 is stored in a compartment that is disengaged from the plasma membrane recycling system in the basal state. In response to insulin, GLUT4 is quantally released from this compartment in a pulsatile manner, leaving some sequestered from the recycling pathway even in conditions of excess insulin. Once disengaged from this location we suggest that in the continuous presence of insulin this quanta of GLUT4 continuously recycles to the plasma membrane, possibly via non-endosomal carriers that are formed at the perinuclear region.
Published: 2004

30. ApoB100-LDL Acts as a Metabolic Signal from Liver to Peripheral Fat Causing Inhibition of Lipolysis in Adipocytes

Author: Josefin Skogsberg, Hasanuzzaman Bhuiyan, Roland Nilsson, Anders Hamsten, Dominique Langin, Sigurd Vitols, Jesper Tegnér, Peter Arner, Johan Björkegren, Gaby Åström, Andrea Dicker, Erik Walum, Peteris Alberts, Mikael Rydén, Aline Mairal, The Computational Medicine Group, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department of medicine [Stockholm], Computational Biology Unit, Linköping University (LIU), Division of Clinical Pharmacology, Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biovitrum AB, Biovitrum, Atherosclerosis Research Unit, This study was supported by grants from the Swedish Research Council (P.Ar. and J.B.), the Swedish Diabetes Association (P.Ar.), the Swedish Heart-Lung Foundation (P.Ar., J.B., and A.H.), the Novo Nordic Foundation (P.Ar.) and the King Gustaf V and Queen Victoria Foundation (P.Ar., J.B.) and the European Commission, 6th Framework Program (contract LSHM-CT-2005-01873)., and Simon, Marie Francoise
Subjects: Male, MESH: Lipoproteins, LDL, Very low-density lipoprotein, Apolipoprotein B, Adipose tissue, White adipose tissue, Cell Biology/Cell Signaling, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: Metabolic Syndrome X, Diabetes and Endocrinology/Endocrinology, Adipocytes, MESH: Animals, Metabolic Syndrome, MESH: Aged, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH: Middle Aged, Multidisciplinary, biology, Chemistry, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Lipoproteins, LDL, MESH: Glucose, Diabetes and Endocrinology, Liver, MESH: Adipose Tissue, White, Apolipoprotein B-100, Medicine, lipids (amino acids, peptides, and proteins), Research Article, Adult, medicine.medical_specialty, Science, Adipose Tissue, White, Lipolysis, 030209 endocrinology & metabolism, 03 medical and health sciences, Lipid oxidation, 3T3-L1 Cells, Internal medicine, medicine, Animals, Humans, MESH: Lipolysis, MESH: Overweight, MESH: Mice, MESH: Adipocytes, Aged, 030304 developmental biology, MESH: Apolipoprotein B-100, MESH: Humans, Cholesterol, MESH: Adult, Overweight, MESH: 3T3-L1 Cells, MESH: Male, Glucose, Endocrinology, LDL receptor, biology.protein, MESH: Liver
Abstract: International audience; BACKGROUND: Free fatty acids released from adipose tissue affect the synthesis of apolipoprotein B-containing lipoproteins and glucose metabolism in the liver. Whether there also exists a reciprocal metabolic arm affecting energy metabolism in white adipose tissue is unknown. METHODS AND FINDINGS: We investigated the effects of apoB-containing lipoproteins on catecholamine-induced lipolysis in adipocytes from subcutaneous fat cells of obese but otherwise healthy men, fat pads from mice with plasma lipoproteins containing high or intermediate levels of apoB100 or no apoB100, primary cultured adipocytes, and 3T3-L1 cells. In subcutaneous fat cells, the rate of lipolysis was inversely related to plasma apoB levels. In human primary adipocytes, LDL inhibited lipolysis in a concentration-dependent fashion. In contrast, VLDL had no effect. Lipolysis was increased in fat pads from mice lacking plasma apoB100, reduced in apoB100-only mice, and intermediate in wild-type mice. Mice lacking apoB100 also had higher oxygen consumption and lipid oxidation. In 3T3-L1 cells, apoB100-containing lipoproteins inhibited lipolysis in a dose-dependent fashion, but lipoproteins containing apoB48 had no effect. ApoB100-LDL mediated inhibition of lipolysis was abolished in fat pads of mice deficient in the LDL receptor (Ldlr(-/-)Apob(100/100)). CONCLUSIONS: Our results show that the binding of apoB100-LDL to adipocytes via the LDL receptor inhibits intracellular noradrenaline-induced lipolysis in adipocytes. Thus, apoB100-LDL is a novel signaling molecule from the liver to peripheral fat deposits that may be an important link between atherogenic dyslipidemias and facets of the metabolic syndrome.
Published: 2008
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31. Transcriptional Control of Brown Fat Determination by PRDM16

Author: Geneviève Tavernier, Lindsay M. Rohas, Dominique Langin, Marc Uldry, Patrick Seale, Sherry Chin, Wenli Yang, Shingo Kajimura, Bruce M. Spiegelman, Simon, Marie Francoise, Dana-Farber Cancer Institute and the Department of Cell Biology, Harward Medical School, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Male, Transcription, Genetic, Physiology, Cellular differentiation, Adipocytes, White, HUMDISEASE, DIO2, Adipose tissue, Electrophoretic Mobility Shift Assay, DEVBIO, White adipose tissue, MESH: Mice, Knockout, Ion Channels, Mice, 0302 clinical medicine, Adipose Tissue, Brown, Genes, Reporter, MESH: Reverse Transcriptase Polymerase Chain Reaction, Chlorocebus aethiops, Adipocytes, MESH: Animals, MESH: Oxygen Consumption, Cells, Cultured, Uncoupling Protein 1, Mice, Knockout, PRDM16, MESH: Adipocytes, Brown, Mice, Inbred C3H, 0303 health sciences, biology, Reverse Transcriptase Polymerase Chain Reaction, MESH: Mitochondrial Proteins, Cell Differentiation, MESH: Transcription Factors, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, MESH: Gene Expression Regulation, Thermogenin, Mitochondria, Cell biology, DNA-Binding Proteins, MESH: COS Cells, Adipocytes, Brown, Phenotype, MESH: Adipose Tissue, White, COS Cells, MESH: Cells, Cultured, MESH: Cell Differentiation, Cellular respiration, MESH: Iodide Peroxidase, MESH: Mice, Transgenic, MESH: Mitochondria, MESH: Trans-Activators, Adipose Tissue, White, Blotting, Western, Cell Respiration, Deiodinase, Mice, Transgenic, MESH: Phenotype, Iodide Peroxidase, MESH: Adipose Tissue, Brown, Article, Mitochondrial Proteins, 03 medical and health sciences, Oxygen Consumption, MESH: Mice, Inbred C57BL, 3T3-L1 Cells, Animals, MESH: Blotting, Western, MESH: Mice, Inbred C3H, Molecular Biology, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: Transcription, Genetic, MESH: Genes, Reporter, Cell Biology, Fibroblasts, Molecular biology, MESH: Cercopithecus aethiops, MESH: 3T3-L1 Cells, MESH: Male, Mice, Inbred C57BL, MESH: Adipocytes, White, Gene Expression Regulation, MESH: Fibroblasts, MESH: Electrophoretic Mobility Shift Assay, MESH: Ion Channels, Trans-Activators, biology.protein, MESH: Cell Respiration, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Transcription Factors
Abstract: International audience; Brown fat cells are specialized to dissipate energy and can counteract obesity; however, the transcriptional basis of their determination is largely unknown. We show here that the zinc-finger protein PRDM16 is highly enriched in brown fat cells compared to white fat cells. When expressed in white fat cell progenitors, PRDM16 activates a robust brown fat phenotype including induction of PGC-1alpha, UCP1, and type 2 deiodinase (Dio2) expression and a remarkable increase in uncoupled respiration. Transgenic expression of PRDM16 at physiological levels in white fat depots stimulates the formation of brown fat cells. Depletion of PRDM16 through shRNA expression in brown fat cells causes a near total loss of the brown characteristics. PRDM16 activates brown fat cell identity at least in part by simultaneously activating PGC-1alpha and PGC-1beta through direct protein binding. These data indicate that PRDM16 can control the determination of brown fat fate.
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32. Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62

Author: A. Rodriguez, Johan Auwerx, Francisco J. Diez-Guerra, Angeles Duran, Mohammed Selloum, Marie-France Champy, Maria T. Diaz-Meco, Manuel Serrano, Jorge Moscat, Juana M. Flores, Instituto de Cerámica y Vidrio (ICV), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)
Subjects: MAPK/ERK pathway, MESH: Signal Transduction, Physiology, medicine.medical_treatment, Cellular differentiation, HUMDISEASE, Adipose tissue, MESH: Mice, Knockout, Mice, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Adipocytes, MESH: Animals, Extracellular Signal-Regulated MAP Kinases, MESH: Extracellular Signal-Regulated MAP Kinases, Mice, Knockout, 0303 health sciences, Adipogenesis, MESH: Transcription Factors, MESH: Insulin Resistance, Adipose Tissue, SIGNALING, 030220 oncology & carcinogenesis, Signal transduction, MESH: Adipose Tissue, MESH: Diabetes Mellitus, Type 2, Signal Transduction, medicine.medical_specialty, Biology, 03 medical and health sciences, Insulin resistance, 3T3-L1 Cells, Internal medicine, medicine, Animals, Humans, RNA, Messenger, Molecular Biology, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Insulin, MESH: Embryo, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Fibroblasts, Embryo, Mammalian, medicine.disease, MESH: 3T3-L1 Cells, MESH: Hela Cells, Endocrinology, Diabetes Mellitus, Type 2, chemistry, MESH: Fibroblasts, Insulin Resistance, Transcription Factor TFIIH, MESH: Adipogenesis, HeLa Cells, Transcription Factors
Abstract: International audience; Signaling cascades that control adipogenesis are essential in the regulation of body weight and obesity. The adaptor p62 controls pathways that modulate cell differentiation. We report here that p62(-/-) mice develop mature-onset obesity, leptin resistance, as well as impaired glucose and insulin intolerance. The metabolic rate was significantly reduced in p62(-/-) nonobese mice, which displayed increased mRNA levels of PPAR-gamma and reduced levels of UCP-1 in adipose tissue. Basal activity of ERK was enhanced in fat from nonobese mutant mice. Embryo fibroblasts from p62(-/-) mice differentiated better than the wild-type controls into adipocytes, which was abrogated by pharmacological inhibition of the ERK pathway. p62 is induced during adipocyte differentiation and inhibits ERK activation by direct interaction. We propose that p62 normally antagonizes basal ERK activity and adipocyte differentiation and that its loss leads to the hyperactivation of ERK that favors adipogenesis and obesity.
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32 results on '"MESH: 3T3-L1 Cells"'

1. Identification of adipocytes as target cells for Leishmania infantum parasites

2. Gene Expression Pattern in Response to Cholecalciferol Supplementation Highlights Cubilin as a Major Protein of 25(OH)D Uptake in Adipocytes and Male Mice White Adipose Tissue

3. Peroxisome Proliferator-activated Receptor γ Regulates Genes Involved in Insulin/Insulin-like Growth Factor Signaling and Lipid Metabolism during Adipogenesis through Functionally Distinct Enhancer Classes

4. DNA damage and the activation of the p53 pathway mediate alterations in metabolic and secretory functions of adipocytes Running title: DNA damage and p53 in obese adipocytes

5. A Possible Inflammatory Role of Twist1 in Human White Adipocytes

6. Interleukin-1β-Induced Insulin Resistance in Adipocytes through Down-Regulation of Insulin Receptor Substrate-1 Expression

7. The Paired Basic Amino Acid-cleaving Enzyme 4 (PACE4) Is Involved in the Maturation of Insulin Receptor Isoform B: an opportunity to reduce the specific insulin receptor-dependent effects of insulin-like growth factor 2 (IGF2)

8. The Paired Basic Amino Acid-cleaving Enzyme 4 (PACE4) Is Involved in the Maturation of Insulin Receptor Isoform B

9. Cdk4 promotes adipogenesis through PPARγ activation

10. Peroxisome proliferator-activated receptor γ regulates genes involved in insulin/insulin-like growth factor signaling and lipid metabolism during adipogenesis through functionally distinct enhancer classes

11. A New Pyrroline Compound Selective for I1-Imidazoline Receptors Improves Metabolic Syndrome in Rats

12. Palmitoylation of TNF alpha is involved in the regulation of TNF receptor 1 signalling

13. Deciphering the role of GLUT4 N-glycosylation in adipocyte and muscle cell models

14. Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers

15. Dimethyl sulfoxide enhances GLUT4 translocation through a reduction in GLUT4 endocytosis in insulin-stimulated 3T3-L1 adipocytes

16. Cyclin G2 regulates adipogenesis through PPAR gamma coactivation

17. Proteasomal degradation of retinoid X receptor alpha reprograms transcriptional activity of PPARgamma in obese mice and humans

18. GLUT4 molecules are recruited at random for insertion within the plasma membrane upon insulin stimulation

19. cyclin G2 and adipocyte differentiation

20. A serum factor induces insulin-independent translocation of GLUT4 to the cell surface which is maintained in insulin resistance

21. Hypoxia decreases insulin signaling pathways in adipocytes

22. Matrix metalloproteinase-11/stromelysin-3 exhibits collagenolytic function against collagen VI under normal and malignant conditions

23. Evidence for an important role of CIDEA in human cancer cachexia

24. Adipogenesis-related increase of semicarbazide-sensitive amine oxidase and monoamine oxidase in human adipocytes

25. The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis

26. In vivo evidence for a role of adipose tissue SR-BI in the nutritional and hormonal regulation of adiposity and cholesterol homeostasis

27. Inhibition of the anti-adipogenic Hedgehog signaling pathway by cyclopamine does not trigger adipocyte differentiation

28. Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma

29. Insulin stimulates the entry of GLUT4 into the endosomal recycling pathway by a quantal mechanism

30. ApoB100-LDL Acts as a Metabolic Signal from Liver to Peripheral Fat Causing Inhibition of Lipolysis in Adipocytes

31. Transcriptional Control of Brown Fat Determination by PRDM16

32. Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62

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32 results on '"MESH: 3T3-L1 Cells"'

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