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1. Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

Author: Armelle Leturque, Agnieszka Blachnio-Zabielska, Véronique Carrière, Sylvie Demignot, Eric Hajduch, Jean-Paul Pais de Barros, Pascal Ferré, Bárbara Graziela Postal, Agnès Ribeiro, Céline Osinski, Monique Rousset, Thi Thu Trang Tran, Centre de Recherche des Cordeliers ( CRC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Medical University of Bialystok, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de Recherche des Cordeliers (CRC), 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), Laboratoire de santé publique et informatique médicale INSERM U872, Université Pierre et Marie Curie - Paris 6 (UPMC), Unité de génétique somatique, Institut Curie [Paris], Plateforme Lipidomique [Dijon] (LAP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Bialystok Med Univ, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), 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), Institut Curie, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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 National de la Recherche Scientifique (CNRS), 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 ), 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 de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Medical University of Białystok (MUB), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
Subjects: 0301 basic medicine, medicine.medical_specialty, Ceramide, medicine.medical_treatment, Palmitic Acid, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Palm Oil, Ceramides, Biochemistry, Palmitic acid, Mice, 03 medical and health sciences, chemistry.chemical_compound, Insulin resistance, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal medicine, medicine, Animals, Humans, Insulin, Plant Oils, Intestinal Mucosa, Phosphorylation, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, biology, Triglyceride, Cell Biology, Lipid signaling, medicine.disease, Lipids, 3. Good health, Insulin receptor, Enterocytes, 030104 developmental biology, Endocrinology, chemistry, Saturated fatty acid, biology.protein, Caco-2 Cells, Proto-Oncogene Proteins c-akt, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: International audience; The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulin-signaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure.
Published: 2016

2. Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions

Author: Erwann Philippe, Athanassia Sotiropoulos, Hervé Le Stunff, Agnieszka Blachnio-Zabielska, Julien Véret, Paola Giussani, Fabienne Foufelle, Cécile L Bandet, Maxime Poirier, Xavier Le Liepvre, Olivier Bourron, Pascal Ferré, Eric Hajduch, Raphaëlle Ballaire, Jan Górski, Dušan Berkeš, Rana Mahfouz, Mélanie Campana, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), 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), Université Paris Diderot - Paris 7 (UPD7), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathogenèse cellulaire et clinique du diabète (CRC - Inserm U1138), 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)-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), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Nutrition, diabète et cerveau, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Bialystok Med Univ, Virologie et Immunologie Moléculaire, Faculté des Sciences Pharmaceutiques, Institut National de la Recherche Agronomique (INRA)-Université Francois Rabelais [Tours], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de diabétologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Slovak University of Technology in Bratislava, Department of Physiology, Medical University of Bialystok, 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), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), 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 National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Medical University of Białystok (MUB), Service de Diabétologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hajduch, Eric, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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), 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)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Adult, Male, Ceramide, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Golgi Apparatus, Mice, Transgenic, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Protein Serine-Threonine Kinases, Ceramides, Endoplasmic Reticulum, 03 medical and health sciences, chemistry.chemical_compound, Mice, Insulin resistance, Internal Medicine, medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Myocyte, Animals, Humans, Insulin, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, biology, Muscles, Fatty Acids, medicine.disease, Sphingolipid, Cell biology, Mice, Inbred C57BL, Insulin receptor, 030104 developmental biology, chemistry, Lipotoxicity, biology.protein, Signal transduction, Insulin Resistance, Signal Transduction
Abstract: International audience; One main mechanism of insulin resistance (IR), a key feature of type 2 diabetes, is the accumulation of saturated fatty acids (FAs) in the muscles of obese patients with type 2 diabetes. Understanding the mechanism that underlies lipid-induced IR is an important challenge. Saturated FAs are metabolized into lipid derivatives called ceramides, and their accumulation plays a central role in the development of muscle IR. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi apparatus through a transporter called CERT, where they are converted into various sphingolipid species. We show that CERT protein expression is reduced in all IR models studied because of a caspase-dependent cleavage. Inhibiting CERT activity in vitro potentiates the deleterious action of lipotoxicity on insulin signaling, whereas overexpression of CERT in vitro or in vivo decreases muscle ceramide content and improves insulin signaling. In addition, inhibition of caspase activity prevents ceramide-induced insulin signaling defects in C2C12 muscle cells. Altogether, these results demonstrate the importance of physiological ER-to-Golgi ceramide traffic to preserve muscle cell insulin signaling and identify CERT as a major actor in this process.
Published: 2018

3. Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes

Author: Catherine Bernard, Aurélie Carlier, Anne-Françoise Batto, Fabienne Foufelle, Olivier Bourron, Nicolas Venteclef, Anaïs Szpigel, Isabelle Hainault, Pascal Ferré, Eric Hajduch, Alain Ktorza, Jean-François Gautier, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC), 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), Laboratoire de Recherche sur les Cultures Anglophones (LARCA UMR 8225), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de physiopathologie de la nutrition (LPN), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), 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)-Sorbonne Université (SU), 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), Service de Diabétologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [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 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 National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de diabétologie [CHU Pitié-Salpétrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), 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 National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]
Subjects: 0301 basic medicine, Ceramide, medicine.medical_specialty, Thioredoxin-Interacting Protein, Inflammasomes, THP-1 Cells, Endocrinology, Diabetes and Metabolism, Inflammation, Type 2 diabetes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Fatty Acids, Monounsaturated, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, NLR Family, Pyrin Domain-Containing 3 Protein, Internal Medicine, medicine, Animals, Humans, Rats, Wistar, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Type 1 diabetes, Dihydroceramide desaturase, Endoplasmic Reticulum Stress, Lipid Metabolism, medicine.disease, Rats, 3. Good health, Oxidative Stress, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, chemistry, 030220 oncology & carcinogenesis, Leukocytes, Mononuclear, Unfolded Protein Response, Unfolded protein response, medicine.symptom, Carrier Proteins, TXNIP
Abstract: Obesity and type 2 diabetes are concomitant with low-grade inflammation affecting insulin sensitivity and insulin secretion. Recently, the thioredoxin interacting protein (TXNIP) has been implicated in the activation process of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. In this study, we aim to determine whether the expression of TXNIP is altered in the circulating immune cells of individuals with type 2 vs type 1 diabetes and whether this can be related to specific causes and consequences of inflammation. The expression of TXNIP, inflammatory markers, markers of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress and enzymes involved in sphingolipid metabolism was quantified by quantitative reverse transcription real-time PCR (qRT-PCR) in peripheral blood mononuclear cells (PBMCs) of 13 non-diabetic individuals, 23 individuals with type 1 diabetes and 81 with type 2 diabetes. A lipidomic analysis on the plasma of 13 non-diabetic individuals, 35 individuals with type 1 diabetes and 94 with type 2 diabetes was performed. The effects of ER stress or of specific lipids on TXNIP and inflammatory marker expression were analysed in human monocyte-derived macrophages (HMDMs) and THP-1 cells. The expression of TXNIP and inflammatory and UPR markers was increased in the PBMCs of individuals with type 2 diabetes when compared with non-diabetic individuals or individuals with type 1 diabetes. TXNIP expression was significantly correlated with plasma fasting glucose, plasma triacylglycerol concentrations and specific UPR markers. Induction of ER stress in THP-1 cells or cultured HMDMs led to increased expression of UPR markers, TXNIP, NLRP3 and IL-1β. Conversely, a chemical chaperone reduced the expression of UPR markers and TXNIP in PBMCs of individuals with type 2 diabetes. The lipidomic plasma analysis revealed an increased concentration of saturated dihydroceramide and sphingomyelin in individuals with type 2 diabetes when compared with non-diabetic individuals and individuals with type 1 diabetes. In addition, the expression of specific enzymes of sphingolipid metabolism, dihydroceramide desaturase 1 and sphingomyelin synthase 1, was increased in the PBMCs of individuals with type 2 diabetes. Palmitate or C2 ceramide induced ER stress in macrophages as well as increased expression of TXNIP, NLRP3 and IL-1β. In individuals with type 2 diabetes, circulating immune cells display an inflammatory phenotype that can be linked to ER stress and TXNIP expression. Immune cell ER stress can in turn be linked to the specific exogenous and endogenous lipid environment found in type 2 diabetes.
Published: 2018

4. Sustained Action of Ceramide on the Insulin Signaling Pathway in Muscle Cells

Author: Hage Hassan, Rima, Pacheco de Sousa, Ana Catarina, Mahfouz, Rana, Hainault, Isabelle, Blachnio-Zabielska, Agnieszka, Bourron, Olivier, Koskas, Fabien, Gorski, Jan, Ferré, Pascal, Foufelle, Fabienne, Hajduch, Eric, 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 de Recherche des Cordeliers (CRC (UMR_S 872)), 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 National de la Recherche Scientifique (CNRS), Bialystok Med Univ, Service de diabétologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Department of Physiology, Medical University of Bialystok, 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), 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), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université
Subjects: [SDV.BC]Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2016

5. Characterising the inhibitory actions of ceramide upon insulin signaling in different skeletal muscle cell models: a mechanistic insight

Author: Nicolas Loiseau, Agnieszka Blachnio-Zabielska, Clare Stretton, Rhéa Khoury, Sophie Turban, Harinder S. Hundal, Rana Mahfouz, Eric Hajduch, Christopher Lipina, Pascal Ferré, Olivier Bourron, Fabienne Foufelle, Centre de Recherche des Cordeliers (CRC), 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), Bialystok Med Univ, University of Dundee, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), College of Life Sciences, Service de diabétologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, 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), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), 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 National de la Recherche Scientifique (CNRS), 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 ), ToxAlim ( ToxAlim ), Institut National Polytechnique [Toulouse] ( INP ) -Institut National de la Recherche Agronomique ( INRA ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse ( ENVT ), Institut National Polytechnique de Toulouse ( INPT ) -Institut National Polytechnique de Toulouse ( INPT ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Medical University of Białystok (MUB), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Societe Francophone du Diabete (ANTADIR grant), Fondation pour Recherche Medicale (Equipe) [FRM DEQ20140329504], Agence Nationale de la Recherche (ANR) [ANR 11 BSV1 03101-Crisalis], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HAL UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de Diabétologie [CHU Pitié-Salpétrière], 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 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Ecosystèmes Insulaires Océaniens (UMR 241) (EIO), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut Louis Malardé [Papeete] (ILM), and Institut de Recherche pour le Développement (IRD)-Université de la Polynésie Française (UPF)
Subjects: Cellular differentiation, Muscle Fibers, Skeletal, lcsh:Medicine, Biochemistry, Mice, chemistry.chemical_compound, Glucose Metabolism, Cell Signaling, Insulin Signaling Cascade, Insulin, Myocyte, Protein Phosphatase 2, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Protein Kinase C, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Myogenesis, Lipids, Signaling Cascades, medicine.anatomical_structure, Carbohydrate Metabolism, Anatomy, Signal transduction, Research Article, Signal Transduction, Cell Physiology, Ceramide, Primary Cell Culture, Muscle Tissue, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Ceramides, Caveolins, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Animals, Humans, Muscle, Skeletal, Protein kinase B, Muscle Cells, Sphingolipids, lcsh:R, Biology and Life Sciences, Skeletal muscle, Cell Biology, Cell Metabolism, Rats, Insulin receptor, Biological Tissue, Metabolism, Gene Expression Regulation, chemistry, biology.protein, lcsh:Q, Proto-Oncogene Proteins c-akt, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Ceramides are known to promote insulin resistance in a number of metabolically important tissues including skeletal muscle, the predominant site of insulin-stimulated glucose disposal. Depending on cell type, these lipid intermediates have been shown to inhibit protein kinase B (PKB/Akt), a key mediator of the metabolic actions of insulin, via two distinct pathways: one involving the action of atypical protein kinase C (aPKC) isoforms, and the second dependent on protein phosphatase-2A (PP2A). The main aim of this study was to explore the mechanisms by which ceramide inhibits PKB/Akt in three different skeletal muscle-derived cell culture models; rat L6 myotubes, mouse C2C12 myotubes and primary human skeletal muscle cells. Our findings indicate that the mechanism by which ceramide acts to repress PKB/Akt is related to the myocellular abundance of caveolin-enriched domains (CEM) present at the plasma membrane. Here, we show that ceramide-enriched-CEMs are markedly more abundant in L6 myotubes compared to C2C12 myotubes, consistent with their previously reported role in coordinating aPKC-directed repression of PKB/Akt in L6 muscle cells. In contrast, a PP2A-dependent pathway predominantly mediates ceramide-induced inhibition of PKB/Akt in C2C12 myotubes. In addition, we demonstrate for the first time that ceramide engages an aPKC-dependent pathway to suppress insulin-induced PKB/Akt activation in palmitate-treated cultured human muscle cells as well as in muscle cells from diabetic patients. Collectively, this work identifies key mechanistic differences, which may be linked to variations in plasma membrane composition, underlying the insulin-desensitising effects of ceramide in different skeletal muscle cell models that are extensively used in signal transduction and metabolic studies.
Published: 2014

6. New insights into ER stress-induced insulin resistance

Author: Eric Hajduch, Pascal Ferré, Fabienne Foufelle, Mélissa Flamment, Laboratoire de Biochimie et Biologie Moléculaire, Université d'Angers (UA), Centre de Recherche des Cordeliers (CRC), 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), 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), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), 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 National de la Recherche Scientifique (CNRS), 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), and 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)
Subjects: medicine.medical_specialty, Lipid accumulation, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Type 2 diabetes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Internal medicine, medicine, Humans, Obesity, Muscle, Skeletal, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Endoplasmic reticulum, Insulin, Endoplasmic Reticulum Stress, Lipid Metabolism, medicine.disease, Adipose Tissue, Diabetes Mellitus, Type 2, Liver, 030220 oncology & carcinogenesis, Insulin signal transduction pathway and regulation of blood glucose, Unfolded Protein Response, Unfolded protein response, Insulin Resistance, Signal Transduction, Transcription Factors
Abstract: Insulin resistance is a major characteristic of obesity and type 2 diabetes (T2DM). During the last decade, endoplasmic reticulum (ER) stress has emerged as a new player in this field and a considerable number of recent studies have pointed out its role in the onset of insulin resistance (IR). ER stress appears to act directly as a negative modulator of the insulin signaling pathway but also indirectly by promoting lipid accumulation. This review aims to summarize and decipher the abundant new literature concerning the emerging and multifaceted involvement of ER stress in the development of metabolic dysfunctions in insulin target tissues.
Published: 2012

7. PPARγ contributes to PKM2 and HK2 expression in fatty liver

Author: Catherine Espeillac, Ganna Panasyuk, Akira Suzuki, Francisco Verdeguer, Lluis Fajas, Céline Chauvin, Jean-Sébastien Annicotte, Marc Foretz, Ludivine A. Pradelli, Jean-Yves Scoazec, Marco Pontoglio, Pascal Ferré, Mario Pende, Morris J. Birnbaum, Jean-Ehrland Ricci, Yasuo Horie, Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anipath, UFR Médecine Lyon-RTH Laennec-UFR Médecine Lyon-RTH Laennec, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, University of Pennsylvania [Philadelphia], Centre méditerranéen de médecine moléculaire (C3M), 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 de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from the European Research Council, from Fondation de la Recherche Medicale (DEQ20061107956) and from Fondation Schlumberger pour l'Education et la Recherche to M.P., and from the Association pour la Recherche sur le Cancer to M.P. and J.-E.R. L.A.P received a fellowship from the Région Provence-Alpes-Cote-d'Azur and INSERM, C.E. from Ministere de Recherche et Technologies and from Fondation de la Recherche Medicale., We are grateful to the members of INSERM-U845 for support, and to David Sabatini, Stefano Fumagalli, Benoit Viollet, Fabienne Foufelle, Renaud Dentin, Pascal Pineau, Isabelle André-Schmutz, Olivier Danos and Anne Dejean for helpful discussions and sharing reagents. We thank Sophie Berissi, Dominique Chretien and Sylvie Fabrega for technical support., Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), 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 ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), 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 National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Anipath, 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), Akita University, Kyushu University, 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), 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 National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tumeurs endocrines digestives : mécanismes de la tumorigenèse et de la progression tumorale, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania, and FORETZ, Marc
Subjects: MESH : Fatty Liver, MESH : Immunohistochemistry, MESH : Insulin, General Physics and Astronomy, Peroxisome proliferator-activated receptor, MESH : Promoter Regions, Genetic, MESH: Thiazolidinediones, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 0302 clinical medicine, Hexokinase, MESH : Cell Proliferation, Insulin, MESH: Hexokinase, MESH: Animals, MESH : Glycolysis, Promoter Regions, Genetic, MESH: Fatty Liver, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, Disease genetics, MESH: Gene Expression Regulation, Enzymologic, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Immunohistochemistry, MESH : Mice, Transgenic, MESH : Thiazolidinediones, MESH : Proto-Oncogene Proteins c-akt, MESH : Thyroid Hormones, Biochemistry, 030220 oncology & carcinogenesis, MESH: Glycolysis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Peroxisome proliferator-activated receptor delta, MESH: Membrane Proteins, Peroxisome proliferator-activated receptor alpha, MESH : Carrier Proteins, Clinical pharmacology, PPARGC1B, Glycolysis, MESH : PPAR gamma, Thyroid Hormones, Peroxisome proliferator-activated receptor gamma, MESH: Mice, Transgenic, Mice, Transgenic, MESH: Carrier Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Insulin, Biology, PKM2, Gene Expression Regulation, Enzymologic, Article, General Biochemistry, Genetics and Molecular Biology, MESH : Gene Expression Regulation, Enzymologic, 03 medical and health sciences, MESH: Thyroid Hormones, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Cell Proliferation, MESH : Mice, MESH: Promoter Regions, Genetic, Animals, Humans, MESH: Mice, Liver diseases, Cell Proliferation, 030304 developmental biology, MESH: Humans, MESH: Proto-Oncogene Proteins c-akt, Liver receptor homolog-1, MESH : Humans, Membrane Proteins, MESH: Immunohistochemistry, General Chemistry, MESH : Hexokinase, Fatty Liver, PPAR gamma, MESH: PPAR gamma, chemistry, MESH : Membrane Proteins, Thiazolidinediones, MESH : Animals, Carrier Proteins, Proto-Oncogene Proteins c-akt, Pyruvate kinase
Abstract: Rapidly proliferating cells promote glycolysis in aerobic conditions, to increase growth rate. Expression of specific glycolytic enzymes, namely pyruvate kinase M2 and hexokinase 2, concurs to this metabolic adaptation, as their kinetics and intracellular localization favour biosynthetic processes required for cell proliferation. Intracellular factors regulating their selective expression remain largely unknown. Here we show that the peroxisome proliferator-activated receptor gamma transcription factor and nuclear hormone receptor contributes to selective pyruvate kinase M2 and hexokinase 2 gene expression in PTEN-null fatty liver. Peroxisome proliferator-activated receptor gamma expression, liver steatosis, shift to aerobic glycolysis and tumorigenesis are under the control of the Akt2 kinase in PTEN-null mouse livers. Peroxisome proliferator-activated receptor gamma binds to hexokinase 2 and pyruvate kinase M promoters to activate transcription. In vivo rescue of peroxisome proliferator-activated receptor gamma activity causes liver steatosis, hypertrophy and hyperplasia. Our data suggest that therapies with the insulin-sensitizing agents and peroxisome proliferator-activated receptor gamma agonists, thiazolidinediones, may have opposite outcomes depending on the nutritional or genetic origins of liver steatosis., Molecular factors, regulating the expression of specific glycolytic enzymes that favour biosynthetic processes, have remained unknown. Panasyuk et al. identify PPARγ as a novel transcription factor turning on pyruvate kinase M2 and hexokinase 2, which are frequently upregulated in pathophysiological growth.
Published: 2012

8. P278 Un régime enrichi en isomères conjugués de l’acide linoléique (CLA) induit une inflammation massive et réversible du tissu adipeux chez la souris

Author: Karine Clément, Michèle Guerre-Millo, Froogh Darakhshan, Hélène Poirier, Elise Dalmas, Annie Quignard-Boulangé, Philippe Besnard, U872 Centre de Recherche des Cordeliers, Nutriomique, Équipe 7, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), 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 National de la Recherche Scientifique (CNRS)-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 National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC), 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), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), 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), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
Subjects: 03 medical and health sciences, Isomères, 0302 clinical medicine, Endocrinology, Régime, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Internal Medicine, 030209 endocrinology & metabolism, General Medicine, Acide linoléique, 030204 cardiovascular system & hematology, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Introduction Chez la souris, un regime enrichi en isomeres conjugues de l’acide linoleique (CLA) provoque une lipodystrophie majeure. Une etude recente (Poirier et al., Diabetes, 2006, 55 : 1634) revele l’accumulation rapide de macrophages dans le tissu adipeux blanc de souris traitees par l’isomere actif, t10, c12-CLA, apres 7 jours de gavage. Nous avons utilise ce modele pour caracteriser la cinetique d’infiltration du tissu adipeux par les differents types de cellules de l’immunite innee et adaptative. Materiels et Methodes Des souris C57Bl/6 ont ete soumises a un regime enrichi en CLA pendant 2, 10 semaines ou 10 semaines suivies de 4 semaines de regime normal. Les cellules immunitaires ont ete detectees par immunohistochimie dans le tissu adipeux retroperitoneal et inguinal. Resultats Un infiltrat de lymphocytes T (CD3 +) et de cellules NK (Ly49 +) apparait des 2 semaines de regime et diminue a 10 semaines. Des macrophages (F4/80 +) et des mastocytes (Tryptase +) sont presents a 2 semaines et s’accumulent massivement a 10 semaines. Le developpement d’une fibrose importante est mis en evidence par coloration au trichome de Masson. A l’arret du regime, la reconstitution rapide des reserves de graisses s’accompagne d’une diminution de tous les types de cellules de l’immunite et de la fibrose. Conclusion En conclusion, l’administration d’un regime enrichi en CLA chez la souris represente un modele d’inflammation aigue et expeditif du tissu adipeux, qui est surprenant par sa reversibilite et qui reproduit certains aspects de la pathologie d’organe associee a l’obesite, malgre l’absence d’hypertrophie adipocytaire.
Published: 2010

9. Lipid droplet analysis in caveolin-deficient adipocytes: alterations in surface phospholipid composition and maturation defects

Author: Anita Eberl, Isabelle Dugail, Harald Köfeler, Olivier Bourron, Françoise Lasnier, Jean François Gautier, Soazig Le Lay, Xavier Le Liepvre, Cédric M. Blouin, Pascal Ferré, Eric Hajduch, Christophe Klein, Ida Chiara Guerrera, Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Medical Research, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), 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)-Sorbonne Université (SU), Service de diabétologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [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), 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), Centre de Recherche des Cordeliers (CRC), 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), Sorbonne Université - Faculté de médecine Pitié Salpétrière, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], 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), CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Sorbonne Université - Faculté de médecine [CHU Pitié Salpétrière], and Service de Diabétologie [CHU Pitié-Salpétrière]
Subjects: lipid storage, endocrine system, obesity, Proteome, [SDV]Life Sciences [q-bio], Caveolin 1, Phospholipid, QD415-436, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Biochemistry, complex mixtures, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Endocrinology, Caveolae, Adipocyte, Lipid droplet, 3T3-L1 Cells, Caveolin, Adipocytes, Animals, Humans, ComputingMilieux_MISCELLANEOUS, phospholipids, 030304 developmental biology, 0303 health sciences, technology, industry, and agriculture, Cell Biology, Lipidome, eye diseases, Cell biology, Rats, chemistry, Perilipin, lipids (amino acids, peptides, and proteins), triacylglycerol, 030217 neurology & neurosurgery, Research Article
Abstract: Caveolins form plasmalemnal invaginated caveolae. They also locate around intracellular lipid droplets but their role in this location remains unclear. By studying primary adipocytes that highly express caveolin-1, we characterized the impact of caveolin-1 deficiency on lipid droplet proteome and lipidome. We identified several missing proteins on the lipid droplet surface of caveolin-deficient adipocytes and showed that the caveolin-1 lipid droplet pool is organized as multi-protein complexes containing cavin-1, with similar dynamics as those found in caveolae. On the lipid side, caveolin deficiency did not qualitatively alter neutral lipids in lipid droplet, but significantly reduced the relative abundance of surface phospholipid species: phosphatidylserine and lysophospholipids. Caveolin-deficient adipocytes can form only small lipid droplets, suggesting that the caveolin-lipid droplet pool might be involved in lipid droplet size regulation. Accordingly, we show that caveolin-1 concentration on adipocyte lipid droplets positively correlated with lipid droplet size in obese rodent models and human adipocytes. Moreover, rescue experiments by caveolin- green fluorescent protein in caveolin-deficient cells exposed to fatty acid overload demonstrated that caveolin-coated lipid droplets were able to grow larger than caveolin-devoid lipid droplets. Altogether, these data demonstrate that the lipid droplet-caveolin pool impacts on phospholipid and protein surface composition of lipid droplets and suggest a functional role on lipid droplet expandability.
Published: 2009

10. 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

11. Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

Author: Gesina, Emilie, Blondeau, Bertrand, Milet, Aude, Le Nin, Isabelle, Duchene, Belinda, Czernichow, Paul, Scharfmann, Raphaël, Tronche, François, Breant, Bernadette, Diabète de l'enfant et développement ((U 690)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Génétique moléculaire, neurophysiologie et comportement, Centre National de la Recherche Scientifique (CNRS), Développement normal et pathologique des organes endocrines (EMI 363), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), FP6 Food-CT-2005-007036 'Earnest', ANR grant N°A05245DS, Juvenile Diabetes Research Fundation, and Breant, Bernadette
Subjects: [SDV.BDD] Life Sciences [q-bio]/Development Biology, glucocorticoid receptor gene": "pancreas": "development": "grafts" :"mice, "glucocorticoid receptor gene": "pancreas": "development": "grafts" :"mice", [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract: AIMS/HYPOTHESIS: Beta cell development is sensitive to glucocorticoid levels. Although direct effects of glucocorticoids on pancreatic precursors have been shown to control beta cell mass expansion, indirect effects of these hormones on pancreatic development remain unexplored. This issue was addressed in mice lacking the glucocorticoid receptor (GR) in the whole organism. MATERIALS AND METHODS: The pancreatic phenotype of GR(null/null) mice was studied at fetal ages (embryonic day [E]) E15.5 and E18 by immunohistochemistry and beta cell fraction measurements. To distinguish between direct and indirect effects, mutant E15.5 fetal pancreata were grafted under the kidney capsule of immunodeficient mice and analysed after 1 week. RESULTS: E18 GR(null/null) fetuses had smaller digestive tracts and tiny pancreata. Massive pancreatic disorganisation and apoptosis were observed despite the presence of all cell types. E15.5 GR(null/null) mutants were indistinguishable from wild-type regarding pancreatic size, tissue structure and organisation, beta cell fraction and production of exocrine transcription factor Ptf1a, neurogenin 3 and Pdx-1. Grafting E15.5 GR(null/null) pancreata into a GR-expressing environment rescued the increased apoptosis and mature islets were observed, suggesting that GR(null/null) pancreatic cell death can be attributed to indirect effects of glucocorticoids on this tissue. Heterozygous GR(+/null) mutants with reduced GR numbers showed no apoptosis but increased beta cell fraction at E18 and the adult age, strengthening the importance of an accurate GR dosage on beta cell mass expansion. CONCLUSIONS/INTERPRETATION: Our results provide evidence for GR involvement in pancreatic tissue organisation and survival through indirect effects. GR does not appear necessary for early phases, but its accurate dosage is critical to modulate beta cell mass expansion at later fetal stages, presumably through direct effects.
Published: 2006

12. Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

Author: Gesina, Emilie, Blondeau, Bertrand, Milet, Aude, Le Nin, Isabelle, Duchene, Belinda, Czernichow, Paul, Scharfmann, Raphaël, Tronche, François, Breant, Bernadette, Diabète de l'enfant et développement ((U 690)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), 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), Génétique moléculaire, neurophysiologie et comportement, Centre National de la Recherche Scientifique (CNRS), Développement normal et pathologique des organes endocrines (EMI 363), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), FP6 Food-CT-2005-007036 'Earnest', ANR grant N°A05245DS, and Juvenile Diabetes Research Fundation
Subjects: glucocorticoid receptor gene": "pancreas": "development": "grafts" :"mice, "glucocorticoid receptor gene": "pancreas": "development": "grafts" :"mice", [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract: AIMS/HYPOTHESIS: Beta cell development is sensitive to glucocorticoid levels. Although direct effects of glucocorticoids on pancreatic precursors have been shown to control beta cell mass expansion, indirect effects of these hormones on pancreatic development remain unexplored. This issue was addressed in mice lacking the glucocorticoid receptor (GR) in the whole organism. MATERIALS AND METHODS: The pancreatic phenotype of GR(null/null) mice was studied at fetal ages (embryonic day [E]) E15.5 and E18 by immunohistochemistry and beta cell fraction measurements. To distinguish between direct and indirect effects, mutant E15.5 fetal pancreata were grafted under the kidney capsule of immunodeficient mice and analysed after 1 week. RESULTS: E18 GR(null/null) fetuses had smaller digestive tracts and tiny pancreata. Massive pancreatic disorganisation and apoptosis were observed despite the presence of all cell types. E15.5 GR(null/null) mutants were indistinguishable from wild-type regarding pancreatic size, tissue structure and organisation, beta cell fraction and production of exocrine transcription factor Ptf1a, neurogenin 3 and Pdx-1. Grafting E15.5 GR(null/null) pancreata into a GR-expressing environment rescued the increased apoptosis and mature islets were observed, suggesting that GR(null/null) pancreatic cell death can be attributed to indirect effects of glucocorticoids on this tissue. Heterozygous GR(+/null) mutants with reduced GR numbers showed no apoptosis but increased beta cell fraction at E18 and the adult age, strengthening the importance of an accurate GR dosage on beta cell mass expansion. CONCLUSIONS/INTERPRETATION: Our results provide evidence for GR involvement in pancreatic tissue organisation and survival through indirect effects. GR does not appear necessary for early phases, but its accurate dosage is critical to modulate beta cell mass expansion at later fetal stages, presumably through direct effects.
Published: 2006

13. Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

Author: F. Tronche, Bernadette Breant, B. Duchene, I. Le Nin, A. Milet, E. Gesina, B. Blondeau, Raphael Scharfmann, Paul Czernichow, Diabète de l'enfant et développement, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 ), Génétique moléculaire, neurophysiologie et comportement, Centre National de la Recherche Scientifique ( CNRS ), Développement normal et pathologique des organes endocrines ( EMI 363 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), FP6 Food-CT-2005-007036 'Earnest', ANR grant N°A05245DS, Juvenile Diabetes Research Fundation, Diabète de l'enfant et développement ((U 690)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Développement normal et pathologique des organes endocrines (EMI 363), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Cell division, Genotype, Endocrinology, Diabetes and Metabolism, glucocorticoid receptor gene": "pancreas": "development": "grafts" :"mice, Embryonic Development, 030209 endocrinology & metabolism, Apoptosis, Mice, SCID, Biology, Polymerase Chain Reaction, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Glucocorticoid receptor, Receptors, Glucocorticoid, Internal medicine, Insulin-Secreting Cells, Internal Medicine, medicine, Animals, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Glucocorticoids, Pancreas, 030304 developmental biology, Mice, Knockout, 0303 health sciences, "glucocorticoid receptor gene": "pancreas": "development": "grafts" :"mice", Mice, Inbred C57BL, medicine.anatomical_structure, Endocrinology, Pancreas Transplantation, Signal transduction, Beta cell, Subrenal Capsule Assay, hormones, hormone substitutes, and hormone antagonists, Glucocorticoid, Cell Division, Hormone, medicine.drug, Signal Transduction
Abstract: AIMS/HYPOTHESIS: Beta cell development is sensitive to glucocorticoid levels. Although direct effects of glucocorticoids on pancreatic precursors have been shown to control beta cell mass expansion, indirect effects of these hormones on pancreatic development remain unexplored. This issue was addressed in mice lacking the glucocorticoid receptor (GR) in the whole organism. MATERIALS AND METHODS: The pancreatic phenotype of GR(null/null) mice was studied at fetal ages (embryonic day [E]) E15.5 and E18 by immunohistochemistry and beta cell fraction measurements. To distinguish between direct and indirect effects, mutant E15.5 fetal pancreata were grafted under the kidney capsule of immunodeficient mice and analysed after 1 week. RESULTS: E18 GR(null/null) fetuses had smaller digestive tracts and tiny pancreata. Massive pancreatic disorganisation and apoptosis were observed despite the presence of all cell types. E15.5 GR(null/null) mutants were indistinguishable from wild-type regarding pancreatic size, tissue structure and organisation, beta cell fraction and production of exocrine transcription factor Ptf1a, neurogenin 3 and Pdx-1. Grafting E15.5 GR(null/null) pancreata into a GR-expressing environment rescued the increased apoptosis and mature islets were observed, suggesting that GR(null/null) pancreatic cell death can be attributed to indirect effects of glucocorticoids on this tissue. Heterozygous GR(+/null) mutants with reduced GR numbers showed no apoptosis but increased beta cell fraction at E18 and the adult age, strengthening the importance of an accurate GR dosage on beta cell mass expansion. CONCLUSIONS/INTERPRETATION: Our results provide evidence for GR involvement in pancreatic tissue organisation and survival through indirect effects. GR does not appear necessary for early phases, but its accurate dosage is critical to modulate beta cell mass expansion at later fetal stages, presumably through direct effects.
Published: 2006

14. Effets de la metformine sur la stéroïdogenèse des cellules de la granulosa de vache : implication de l'AMP-activated protein kinase (AMPK)?

Author: Tosca, Lucie, Chabrolle, Christine, Ferre, P., Foufelle, F., Uzbekova, Svetlana, Dupont, Joëlle, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), 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 National de la Santé et de la Recherche Médicale (INSERM), ProdInra, Migration, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], AMPK, [SDV]Life Sciences [q-bio], AMP-ACTIVATED PROTEINE KINASE, [INFO]Computer Science [cs], [INFO] Computer Science [cs], ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2006

15. Metformin-induced stimulation of adenosine 5' monophosphate-activated protein kinase (PRKA) impairs progesterone secretion in rat granulosa cells

Author: Tosca, Lucie, Solnais, Patricia, Ferre, P., Foufelle, F., Dupont, Joëlle, ProdInra, Migration, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), 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 National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: CELLULE DE GRANULOSA, FSH, RAT, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, PROGESTERONE, ComputingMilieux_MISCELLANEOUS, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract: International audience
Published: 2006

16. The adipose Renin-Angiotensin system modulates systemic markers of insulin sensitivity and activates the intrarenal Renin-Angiotensin system

Author: Annie Quignard-Boulangé, Jung Han Kim, Naima Moustaid-Moussa, Brynn H. Voy, Suyeon Kim, Morvarid Soltani-Bejnood, Michèle Teboul, Gérard Ailhaud, Florence Massiera, Dept. Nutrition and Agricultural Experiment Station, Knoxville, The University of Tennessee [Knoxville], 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), 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), Life Sciences Division [Oak Ridge], Oak Ridge National Laboratory [Oak Ridge] (ORNL), UT-Battelle, LLC-UT-Battelle, LLC, 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: medicine.medical_specialty, Article Subject, Health, Toxicology and Mutagenesis, Adipose tissue macrophages, medicine.medical_treatment, lcsh:Biotechnology, Adipose tissue, lcsh:Medicine, White adipose tissue, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, lcsh:TP248.13-248.65, Renin–angiotensin system, parasitic diseases, Genetics, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030304 developmental biology, 0303 health sciences, Kidney, Insulin, Leptin, lcsh:R, General Medicine, Endocrinology, medicine.anatomical_structure, Molecular Medicine, Resistin, hormones, hormone substitutes, and hormone antagonists, Biotechnology, Research Article
Abstract: Background. The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism.Methods and results. A panel of mouse models including mice lacking angiotensinogen,Agt(Agt-KO), mice expressingAgtsolely in adipose tissue (aP2-Agt/Agt-KO), and mice overexpressingAgtin adipose tissue (aP2-Agt) was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased inAgt-KO mice, while plasma adiponectin levels were increased. aP2-Agtmice exhibited increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also elevated in kidney of aP2-Agtmice.Conclusion. These findings demonstrate that alterations in adipose RAS activity significantly impact both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.
Published: 2006

17. Action et sécrétion de l'insuline : double jeu pour les canaux potassiques

Author: Ferré, Pascal, 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), and Maylin, Françoise
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Glucose, MESH: Humans, MESH: Islets of Langerhans, MESH: Models, Biological, MESH: Animals, MESH: Insulin, MESH: Potassium Channels, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Published: 2005

18. SREBF-1 gene polymorphisms are associated with obesity and type 2 diabetes in French obese and diabetic cohorts

Author: Annie Le Gall, Arnaud Basdevant, David Meyre, Karine Clément, Delphine Eberlé, Pascal Ferré, Martine Vaxillaire, Fabienne Foufelle, Philippe Froguel, Mourad Sahbatou, Déterminants Biologiques et Comportementaux des Obésités, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-EA3502, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Service de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de l'Hôtel-Dieu, Nutrition et obésité : approches génétique et transcriptomique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Pathologies nutritionnelles et métaboliques : obésité et diabète, Section of Genomic Medicine, Imperial College London, Genome Centre, Imperial College London-Hammersmith campus, and EA3502-Hôtel-Dieu-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Adult, Candidate gene, medicine.medical_specialty, MESH: Hyperlipidemias, MESH: Diabetes Mellitus, Endocrinology, Diabetes and Metabolism, Hyperlipidemias, Single-nucleotide polymorphism, Type 2 diabetes, Biology, MESH: CCAAT-Enhancer-Binding Proteins, Cohort Studies, Exon, MESH: Sterol Regulatory Element Binding Protein 1, Gene Frequency, Internal medicine, MESH: Child, MESH: Polymorphism, Genetic, Diabetes Mellitus, Internal Medicine, Genetic predisposition, medicine, MESH: Gene Frequency, Humans, MESH: Obesity, Obesity, Child, MESH: Cohort Studies, Genetics, Polymorphism, Genetic, MESH: Humans, Haplotype, MESH: Adult, MESH: Transcription Factors, medicine.disease, DNA-Binding Proteins, MESH: France, Endocrinology, Diabetes Mellitus, Type 2, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, CCAAT-Enhancer-Binding Proteins, France, Sterol Regulatory Element Binding Protein 1, Dyslipidemia, MESH: DNA-Binding Proteins, Transcription Factors, MESH: Diabetes Mellitus, Type 2
Abstract: Sterol regulatory element–binding protein (SREBP)-1 transcription factors play a central role in energy homeostasis by promoting glycolysis, lipogenesis, and adipogenesis. The sterol regulatory element–binding protein gene (SREBF)-1 is a good candidate gene for obesity and obesity-related metabolic traits such as type 2 diabetes and dyslipidemia. The SREBF-1 molecular screening of 40 unrelated obese patients by PCR/single-strand conformation polymorphism revealed 19 single nucleotide polymorphisms (SNPs). Six SNPs were genotyped for an association study in large French obese and nonobese cohorts. Case-control studies using two independent nonobese cohorts indicated that SNP17 (54G/C, exon 18c) is associated with morbid obesity (odds ratio 1.5, P = 0.006 and P = 0.02, respectively). SNP3 (−150G/A, exon 1a), SNP5 (−36delG, exon 1a), and SNP17 are found in high linkage disequilibrium (D′ > 0.8). The haplotype including wild-type alleles of these SNPs (C/G/G/T/C/G, HAP2) is identified as a risk factor for morbid obesity (P = 0.003). In the obese group, SNP3, SNP5, and SNP17 are associated with male-specific hypertriglyceridemia (P = 0.07, P = 0.01, and P = 0.05, respectively). SNP17 is also associated with type 2 diabetes (P = 0.03) and increased prevalence of nephropathy (P = 0.028) in a diabetic cohort. Our results indicate a role of the SREBF-1 gene in genetic predisposition of metabolic diseases such as obesity, type 2 diabetes, and dyslipidemia.
Published: 2004

19. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase

Author: Barbara B. Kahn, Yoichi M. Ito, Yasuhiko Minokoshi, S. Uchida, Pascal Ferré, Shigeko Kimura, Shigeo Yamashita, Mitsuhiko Noda, Junji Kamon, Koji Eto, Y. Akanuma, Shunbun Kita, David Carling, Ryozo Nagai, Hironori Waki, Fabienne Foufelle, Takashi Kadowaki, Philippe Froguel, K Ueki, Toshimasa Yamauchi, Kyushu University [Fukuoka], Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Section of Genomic Medicine, Imperial College London, Genome Centre, Imperial College London-Hammersmith campus, 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 Mathématiques de Jussieu (IMJ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Kyushu University
Subjects: Male, MESH: Oxidation-Reduction, Glucose uptake, MESH: Hepatocytes, chemistry.chemical_compound, Mice, 0302 clinical medicine, AMP-activated protein kinase, Adiponectin secretion, MESH: Proteins, MESH: Animals, Phosphorylation, Adiponectin receptor 1, 0303 health sciences, Adiponectin receptor 2, MESH: Muscle, Skeletal, biology, Fatty Acids, General Medicine, MESH: Adiponectin, AdipoRon, MESH: Fatty Acids, MESH: Glucose, Intercellular Signaling Peptides and Proteins, Adiponectin, Oxidation-Reduction, medicine.medical_specialty, MESH: Enzyme Activation, 030209 endocrinology & metabolism, MESH: Cyclic AMP-Dependent Protein Kinases, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, medicine, Animals, Muscle, Skeletal, MESH: Intercellular Signaling Peptides and Proteins, MESH: Mice, 030304 developmental biology, MESH: Phosphorylation, AMPK, Proteins, Cyclic AMP-Dependent Protein Kinases, MESH: Male, Enzyme Activation, Mice, Inbred C57BL, Endocrinology, Glucose, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Hepatocytes, MESH: Acetyl-CoA Carboxylase, Acetyl-CoA Carboxylase
Abstract: Adiponectin (Ad) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. However, the signaling pathways that mediate the metabolic effects of Ad remain poorly identified. Here we show that phosphorylation and activation of the 5'-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full-length Ad in the liver. In parallel with its activation of AMPK, Ad stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty-acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK. Our data may provide a novel paradigm that an adipocyte-derived antidiabetic hormone, Ad, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
Published: 2002

20. Sterol Regulatory Element-binding Protein-1c Mimics the Negative Effect of Insulin on Phosphoenolpyruvate Carboxykinase (GTP) Gene Transcription

Author: Dominique Bécard, Fabienne Foufelle, Patrick Leahy, Pascal Ferré, Richard W. Hanson, Marc Foretz, Kaushik Chakravarty, Parvin Hakimi, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and 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 National de la Recherche Scientifique (CNRS)
Subjects: Cyclic AMP Receptor Protein, Transcription, Genetic, RNA polymerase II, Biochemistry, MESH: CCAAT-Enhancer-Binding Proteins, MESH: Hepatocytes, E2F1, Insulin, MESH: Animals, 0303 health sciences, biology, MESH: Phosphoenolpyruvate Carboxykinase (GTP), 030302 biochemistry & molecular biology, MESH: Transcription Factors, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Activating transcription factor 2, DNA-Binding Proteins, TAF2, Female, Phosphoenolpyruvate Carboxykinase (GTP), lipids (amino acids, peptides, and proteins), Sterol Regulatory Element Binding Protein 1, endocrine system, MESH: Rats, E-box, MESH: Carrier Proteins, MESH: Cyclic AMP-Dependent Protein Kinases, MESH: Insulin, digestive system, 03 medical and health sciences, MESH: Sterol Regulatory Element Binding Protein 1, Sp3 transcription factor, Animals, RNA, Messenger, Rats, Wistar, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, 030304 developmental biology, MESH: RNA, Messenger, ATF3, MESH: Transcription, Genetic, Promoter, MESH: Cyclic AMP Receptor Protein, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: Rats, Wistar, Molecular biology, Cyclic AMP-Dependent Protein Kinases, Rats, biology.protein, CCAAT-Enhancer-Binding Proteins, Hepatocytes, Carrier Proteins, MESH: Female, MESH: DNA-Binding Proteins, Transcription Factors
Abstract: International audience; We have assessed the potential role of sterol regulatory element-binding protein-1c (SREBP-1c) on the transcription of the gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC ) (PEPCK-C). SREBP-1c introduced into primary hepatocytes with an adenovirus vector caused a total loss of PEPCK-C mRNA and a marked induction of fatty acid synthase mRNA that directly coincided with the appearance of SREBP-1c in the hepatocytes. It also blocked the induction of PEPCK-C mRNA by cAMP and dexamethasone in these cells. In contrast, a dominant negative form of SREBP-1c (dnSREBP-1c) stimulated the accumulation of PEPCK-C mRNA in these cells. SREBP-1c completely blocked the induction of PEPCK-C gene transcription by the catalytic subunit of protein kinase A (PKA), and increasing concentrations of dnSREBP-1c reversed the negative effect of insulin on transcription from the PEPCK-C gene promoter in WT-IR cells. The more than 10-fold induction of PKA-stimulated PEPCK-C gene transcription caused by the co-activator CBP, was also blocked by SREBP-1c. In addition, dnSREBP-1c reversed the strong negative effect of E1A and NF1 on PKA-stimulated transcription from the PEPCK-C gene promoter. An analysis of the possible site of action of SREBP-1c using stepwise truncations of the PEPCK-C gene promoter indicated that the negative effect of SREBP-1c on transcription is exerted at a site between -355 and -277. We conclude that SREBP-1c is an intermediate in the action of insulin on PEPCK-C gene transcription in the liver and acts by blocking the stimulatory effect cAMP that is mediated via an interaction with cAMP-binding protein.
Published: 2001

21. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes

Author: Pascal Ferré, Fabienne Foufelle, Marc Foretz, Colette Guichard, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Pathologies nutritionnelles et métaboliques : obésité et diabète, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: DNA Primers, medicine.medical_specialty, MESH: Rats, medicine.medical_treatment, 030209 endocrinology & metabolism, MESH: Insulin, Carbohydrate metabolism, MESH: Base Sequence, MESH: CCAAT-Enhancer-Binding Proteins, 03 medical and health sciences, MESH: Sterol Regulatory Element Binding Protein 1, 0302 clinical medicine, Insulin receptor substrate, Internal medicine, medicine, MESH: Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, 0303 health sciences, Multidisciplinary, biology, Glucokinase, Insulin, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Glucokinase, MESH: Rats, Wistar, MESH: Transcription Factors, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Biological Sciences, MESH: Gene Expression Regulation, MESH: Fatty Acids, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: Glucose, Insulin receptor, Fatty acid synthase, Endocrinology, Lipogenesis, biology.protein, Sterol Regulatory Element Binding Protein 1, lipids (amino acids, peptides, and proteins), MESH: Nuclear Proteins, MESH: Female, MESH: DNA-Binding Proteins, MESH: Liver, MESH: Cells, Cultured, MESH: Fatty Acid Synthases
Abstract: International audience; Hepatic glucokinase plays a key role in glucose metabolism as underlined by the anomalies associated with glucokinase mutations and the consequences of tissue-specific knock-out. In the liver, glucokinase transcription is absolutely dependent on the presence of insulin. The cis-elements and trans-acting factors that mediate the insulin effect are presently unknown; this is also the case for most insulin-responsive genes. We have shown previously that the hepatic expression of the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) is activated by insulin. We show here in primary cultures of hepatocytes that the adenovirus-mediated transduction of a dominant negative form of SREBP-1c inhibits the insulin effect on endogenous glucokinase expression. Conversely, in the absence of insulin, the adenovirus-mediated transduction of a dominant positive form of SREBP-1c overcomes the insulin dependency of glucokinase expression. Hepatic fatty acid synthase and Spot-14 are insulin/glucose-dependent genes. For this latter class of genes, the dominant positive form of SREBP-1c obviates the necessity for the presence of insulin, whereas glucose potentiates the effect of SREBP-1c on their expression. In addition, the insulin dependency of lipid accumulation in cultured hepatocytes is overcome by the dominant positive form of SREBP-1c. We propose that SREBP-1c is a major mediator of insulin action on hepatic gene expression and a key regulator of hepatic glucose/lipid metabolism.
Published: 1999

22. Polyunsaturated fatty acids inhibit fatty acid synthase and spot-14-protein gene expression in cultured rat hepatocytes by a peroxidative mechanism

Author: Marc Foretz, Fabienne Foufelle, Pascal Ferré, Centre de Recherche des Cordeliers (CRC), 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), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and FORETZ, Marc
Subjects: [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, MESH: Lipid Peroxidation, Lipid peroxidation, chemistry.chemical_compound, 0302 clinical medicine, Gene expression, MESH: Animals, MESH: Proteins, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Lipid Metabolism, chemistry.chemical_classification, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, biology, food and beverages, Nuclear Proteins, MESH: Transcription Factors, MESH: Fatty Acids, Unsaturated, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Gene Expression Regulation, Fatty acid synthase, Liver, 030220 oncology & carcinogenesis, Fatty Acids, Unsaturated, lipids (amino acids, peptides, and proteins), Female, Polyunsaturated fatty acid, MESH: Fatty Acid Synthases, Research Article, MESH: Rats, 03 medical and health sciences, Lactate dehydrogenase, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Rats, Wistar, Molecular Biology, 030304 developmental biology, Albumin, Proteins, Lipid metabolism, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: Rats, Wistar, Lipid Metabolism, In vitro, eye diseases, Rats, chemistry, Gene Expression Regulation, biology.protein, sense organs, Lipid Peroxidation, Fatty Acid Synthases, MESH: Female, MESH: Nuclear Proteins, MESH: Liver, Transcription Factors
Abstract: International audience; In vivo, polyunsaturated fatty acids (PUFA) inhibit the expression of hepatic genes related to the lipogenic process such as fatty acid synthase and spot-14-protein (S14) genes. In vitro studies have suggested that this was a direct transcriptional effect of PUFA. In hepatocytes, the inhibition of the lipogenic rate by PUFA is not specific, but is linked to a cytotoxic effect due to peroxidative mechanisms. We have investigated whether peroxidation could also explain the inhibitory effect of PUFA on gene expression. Rat hepatocytes were cultured for 24 h with mono-unsaturated or PUFA. PUFA inhibited the expression of fatty acid synthase and S14 genes, and this inhibition was directly related to the number of unsaturations. However, the beta-actin and albumin mRNA concentrations were also affected by the most unsaturated fatty acids, suggesting a non-specific effect of PUFA on gene expression. Measurement of lactate dehydrogenase released into the medium indicated a cytotoxicity of PUFA. This was associated with their peroxidation as evaluated by the presence of thiobarbituric acid-reactive substances in the culture medium. The addition of high concentrations of antioxidants abolished lipid peroxidation and lactate dehydrogenase leakage and completely reversed the inhibitory effect of PUFA on gene expression. This suggests (i) that the results obtained previously in cultured hepatocytes in the presence of low concentrations of antioxidants must be interpretated cautiously and (ii) that in vivo, the inhibitory effect of PUFA on lipogenesis-related genes could be indirect through hormonal or metabolic changes or that their effect on gene expression is somehow linked to peroxidative mechanisms.
Published: 1999

23. Discrete brain areas express the insulin-responsive glucose transporter GLUT4

Author: Leloup, Corinne, Arluison, M., Kassis, N., Lepetit, N., Cartier, N., Ferre, P., Pénicaud, Luc, Neurobiologie des signaux intercellulaires (NSI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de physiopathologie de la nutrition (LPN), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), 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), Neurobiologie, plasticité tissulaire et métabolisme énergétique (NPTME), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 1996

24. Study of the regulation by nutrients of the expression of genes involved in lipogenesis and obesity in humans and animals

Author: Delzenne, N., Ferre, P., Beylot, M., Daubioul, C., Declercq, B., Diraison, F., Dugail, I., Foufelle, F., Marc FORETZ, Mace, K., Reimer, R., Palmer, G., Rutter, G., Tavare, J., Loo, J., Vidal, H., FORETZ, Marc, Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain = Catholic University of Louvain (UCL), 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), Physiopathologie Metabolique et Renale, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie endocrinienne (U197), Centre de Recherche des Cordeliers (CRC), 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), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), and 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)
Subjects: MESH: Dietary Carbohydrates, MESH: Rats, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Dietary Carbohydrates, Animals, Humans, MESH: Obesity, MESH: Animals, Obesity, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Humans, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Lipids, MESH: Gene Expression Regulation, MESH: Lipids, Rats, Adipose Tissue, Gene Expression Regulation, Liver, Fatty Acid Synthases, MESH: Adipose Tissue, MESH: Fatty Acid Synthases, MESH: Liver
Abstract: International audience; Dietary digestible carbohydrates are able to modulate lipogenesis, by modifying the expression of genes coding for key lipogenic enzymes, like fatty acid synthase. The overall objective of the Nutrigene project (FAIR-CT97-3011) was to study the efficiency of various carbohydrates to modulate the lipogenic capacity and relevant gene expression in rat and human species (control and obese subjects) and to understand the underlying molecular mechanisms involved in the regulation of lipogenic genes by carbohydrates. Key cellular mediators (namely SREBP-1c and 2, AMP activated protein kinase, cholesterol content) of the regulation of lipogenic gene expression by glucose and/or insulin were identified and constitute new putative targets in the development of plurimetabolic syndrome associated with obesity. In humans, hepatic lipogenesis and triglyceride synthesis, assessed in vivo by the use of stable isotopes, was promoted by a high-carbohydrate diet in non obese subjects, and in non alcoholic steatotic patients, but was not modified in the adipose tissue of obese subjects. Non digestible/fermentable carbohydrates, such as fructans, were shown to decrease hepatic lipogenesis in non obese rats, and to lessen hepatic steatosis and body weight in obese Zucker rats. If confirmed in obese humans, this would allow the development of functional food able to counteract the metabolic disturbances linked to obesity.

25. Induction of fatty acid synthase and S14 gene expression by glucose, xylitol and dihydroxyacetone in cultured rat hepatocytes is closely correlated with glucose 6-phosphate concentrations

Author: Florence Mourrieras, Marc Foretz, Fabienne Foufelle, Pascal Ferré, Sandrine Bouche, Joëlle Morin, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Microbiologie de l’Environnement (LME), Institut National de la Recherche Agronomique (INRA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), 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), 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 National de la Recherche Scientifique (CNRS), Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA)
Subjects: Aging, Metabolite, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Glucokinase, Glycolysis, MESH: Aging, MESH: Animals, MESH: Proteins, Cells, Cultured, Xylitol, 0303 health sciences, Nuclear Proteins, MESH: Transcription Factors, MESH: Glucokinase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Glucose-6-Phosphate, MESH: Gene Expression Regulation, MESH: Glucose, Fatty acid synthase, Liver, Enzyme Induction, MESH: Glycolysis, Dihydroxyacetone, Female, Phosphoenolpyruvate carboxykinase, MESH: Cells, Cultured, MESH: Fatty Acid Synthases, Research Article, Snf3, MESH: Enzyme Induction, MESH: Rats, Glucose-6-Phosphate, 030209 endocrinology & metabolism, Pentose phosphate pathway, Biology, 03 medical and health sciences, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Rats, Wistar, Molecular Biology, 030304 developmental biology, MESH: Dihydroxyacetone, MESH: Xylitol, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: Rats, Wistar, Rats, Glucose, chemistry, Glucose 6-phosphate, Gene Expression Regulation, biology.protein, Fatty Acid Synthases, MESH: Nuclear Proteins, MESH: Female, MESH: Liver, Transcription Factors
Abstract: International audience; It is now well established that the transcription of several genes belonging to the glycolytic and lipogenic pathway is stimulated in the presence of a high glucose concentration in adipocytes and hepatocytes. We have previously proposed that glucose 6-phosphate could be the signal metabolite that transduces the glucose effect. This proposal has recently been challenged and both an intermediate of the pentose phosphate pathway, xylulose 5-phosphate, and metabolites of the later part of glycolysis (3-phosphoglycerate and phosphoenolpyruvate) have been proposed. To discriminate between these possibilities, we have measured concomitantly, in primary cultures of adult rat hepatocytes, the expression of the fatty acid synthase (FAS) and S14 genes and the concentration of glucose metabolites. We have used various substrates entering at different steps of the glycolytic pathway (glucose, dihydroxyacetone) and the pentose phosphate pathway (xylitol). When compared with 5 mM glucose, 25 mM glucose induces a marked increase in both S14 and FAS gene expression, detectable as early as 2 h and peaking at 6 h. Increasing concentrations (1-5 mM) of xylitol and dihydroxyacetone in the presence of 5 mM glucose are also able to induce S14 and FAS gene expression progressively. Among the various glucose metabolites measured, glucose 6-phosphate, in contrast with xylulose 5-phosphate and metabolites of the lower part of glycolysis, is the only one that shows a clear-cut parallelism between its concentration and the degree of S14 and FAS gene expression. We conclude that glucose 6-phosphate is the most likely signal metabolite for the glucose-induced transcription of this group of genes.

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25 results on '"Pathologies nutritionnelles et métaboliques : obésité et diabète"'

1. Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

2. Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions

3. Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes

4. Sustained Action of Ceramide on the Insulin Signaling Pathway in Muscle Cells

5. Characterising the inhibitory actions of ceramide upon insulin signaling in different skeletal muscle cell models: a mechanistic insight

6. New insights into ER stress-induced insulin resistance

7. PPARγ contributes to PKM2 and HK2 expression in fatty liver

8. P278 Un régime enrichi en isomères conjugués de l’acide linoléique (CLA) induit une inflammation massive et réversible du tissu adipeux chez la souris

9. Lipid droplet analysis in caveolin-deficient adipocytes: alterations in surface phospholipid composition and maturation defects

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

11. Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

12. Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

13. Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

14. Effets de la metformine sur la stéroïdogenèse des cellules de la granulosa de vache : implication de l'AMP-activated protein kinase (AMPK)?

15. Metformin-induced stimulation of adenosine 5' monophosphate-activated protein kinase (PRKA) impairs progesterone secretion in rat granulosa cells

16. The adipose Renin-Angiotensin system modulates systemic markers of insulin sensitivity and activates the intrarenal Renin-Angiotensin system

17. Action et sécrétion de l'insuline : double jeu pour les canaux potassiques

18. SREBF-1 gene polymorphisms are associated with obesity and type 2 diabetes in French obese and diabetic cohorts

19. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase

20. Sterol Regulatory Element-binding Protein-1c Mimics the Negative Effect of Insulin on Phosphoenolpyruvate Carboxykinase (GTP) Gene Transcription

21. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes

22. Polyunsaturated fatty acids inhibit fatty acid synthase and spot-14-protein gene expression in cultured rat hepatocytes by a peroxidative mechanism

23. Discrete brain areas express the insulin-responsive glucose transporter GLUT4

24. Study of the regulation by nutrients of the expression of genes involved in lipogenesis and obesity in humans and animals

25. Induction of fatty acid synthase and S14 gene expression by glucose, xylitol and dihydroxyacetone in cultured rat hepatocytes is closely correlated with glucose 6-phosphate concentrations

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