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1. Stress exposure alters brain mRNA expression of the genes involved in insulin signalling, an effect modified by a high fat/high fructose diet and cinnamon supplement.

Author

Frédéric Canini, Bolin Qin, Nathalie Arvy, Laurent Poulet, Cécile Batandier, Anne-Marie Roussel, and Richard A Anderson

Subjects
Medicine, Science
Abstract

In occidental societies, high fat and high sugar diets often coincide with episodes of stress. The association is likely to modify brain energy control. Brain insulin signalling is rarely studied in stressed individuals consuming high fat diets. Furthermore the effects of cinnamon supplement are not known in these conditions. Therefore, we exposed rats, over a 12-week period, to a control (C) or a high fat/high fructose (HF/HFr) diet that induces peripheral insulin resistance. A cinnamon supplement (C+CN and HF/HFr +CN) was added or not. After diet exposure, one group of rats was exposed to a 30-min restraint followed by a 10-min open-field test, their combination featuring a moderate stressor, the other rats staying unstressed in their home cages. The insulin signalling in hippocampus and frontal cortex was studied through the mRNA expression of the following genes: insulin receptor (Ir), insulin receptor substrate (Irs1), glucose transporters (Glut1 and Glut3), glycogen synthase (Gys1) and their modulators, Akt1 and Pten. In C rats, stress enhanced the expression of Ir, Irs1, Glut1, Gys1 and Akt1 mRNA. In C+CN rats, stress induced an increase in Pten but a decrease in Gys1 mRNA expression. In HF/HFr rats, stress was associated with an increase in Pten mRNA expression. In HF/HFr+CN rats, stress increased Pten mRNA expression but also decreased Gys1 mRNA expression. This suggests that a single moderate stress favours energy refilling mechanisms, an effect blunted by a previous HF/HFr diet and cinnamon supplement.

Published
2018
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2. Manganese Cytotoxicity Assay on Hippocampal Neuronal Cell Culture

Author

Alexia Daoust, Yasmina Saoudi, Jacques Brocard, Nora Collomb, Cécile Batandier, Mariano Bisbal, Murielle Salomé, Annie Andrieux, Sylvain Bohic, and Emmanuel Barbier

Subjects
Biology (General), QH301-705.5
Abstract

Compared to an in vivo experiment, neuronal cell cultures are immediately accessible to observation and manipulation. In this protocol, we describe a technique to evaluate the cytotoxicity of a metal, manganese (Mn2+), on hippocampal neuronal cell cultures. Interestingly, this protocol is easily adaptable to any type of primary culture (e.g., cortical neurons) and any type of toxic compound (e.g., chemical product).This protocol is similar to "Neuron-enriched Cultures (Method 2)" protocol (Gao, 2011).

Published
2015
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3. Maternal exercise before and during gestation modifies liver and muscle mitochondria in rat offspring

Author

Anne Galinier, Hervé Dubouchaud, Isabelle Hininger, C. Quiclet, Eric Fontaine, Louis Casteilla, Guillaume Vial, Cécile Batandier, Farida Siti, Karine Couturier, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), University Hospital Jakarta, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-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-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes - UFR Activités physiques et sportives (UGA UFR APS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Universitas Indonesia (UI ), Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2 ), Hamant, Sarah, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0106 biological sciences, Male, medicine.medical_specialty, Intrauterine environment, Physiology, Offspring, 030310 physiology, [SDV]Life Sciences [q-bio], Mothers, Mitochondria, Liver, Aquatic Science, Biology, Mitochondrion, Oxidative phosphorylation, Protein oxidation, 010603 evolutionary biology, 01 natural sciences, 03 medical and health sciences, Endurance training, Pregnancy, Internal medicine, Physical Conditioning, Animal, medicine, Animals, Rats, Wistar, Muscle, Skeletal, Molecular Biology, Ecology, Evolution, Behavior and Systematics, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, 0303 health sciences, Fetus, Skeletal muscle, medicine.disease, Hindlimb, Mitochondria, Rats, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Endocrinology, Liver, Insect Science, Gestation, Animal Science and Zoology, Female
Abstract

It is now well established that the intrauterine life environment is of major importance for health during later life. Endurance training during pregnancy is associated with positive metabolic adjustments and beneficial effects on the balance between pro and antioxidant (redox state) in the offspring. Our hypothesis is that these changes could rely on mitochondrial adaptations in the offspring due to modifications of the fetal environment induced by maternal endurance training. Therefore, we compared the liver and skeletal muscle mitochondrial function and the redox status of young rats whose mothers underwent moderate endurance training (treadmill running) before and during gestation (T) to those of young rats from untrained mothers (C). Our results show a significant reduction in the spontaneous H2O2 release by liver and muscle mitochondria in the T vs. C rats (p In plasma, GPX activity and protein oxidation are significantly higher in T rats compared to C rats (p We demonstrated for the first time, to our knowledge, that it is possible to act on the bioenergetic functionning including alterations of the mitochondrial function in the offspring by modifying maternal physical activity before and during pregnancy. These changes could be crucial for the future health of the offspring.

Published
2019

4. Unexpected metabolic disorders induced by endocrine disruptors in Xenopus tropicalis provide new lead for understanding amphibian decline

Author

Muriel Raveton, Anne-Laure Bulteau, Bruno Combourieu, David Lejon, Thomas Lafond, Cédric Le May, Christophe Regnault, Karine Couturier, Maud Chétiveaux, Cécile Batandier, Sylvie Veyrenc, Alexandre Sapin, Marie Usal, Stéphane Reynaud, Laboratoire d'Ecologie Alpine (LECA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Joseph Fourier - Grenoble 1 (UJF)-Université Grenoble Alpes (UGA), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Pôle de Recherche ROVALTAIN, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Ressources Biologiques Xénopes, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Projet IRS 2017 - IDEX-UGA : Effets métaboliques transgénérationnels des perturbateurs endocriniens sur les amphibiens : rôle dans le déclin des populations., CHATEL, Stephanie, Laboratoire d'Ecologie Alpine (LECA ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Fondation de Coopération Scientifique ROVALTAIN, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Rennes (UR), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
0301 basic medicine, Amphibian, medicine.medical_specialty, medicine.medical_treatment, media_common.quotation_subject, Xenopus, Biology, metabolic syndrome, Transcriptome, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, biology.animal, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Endocrine system, Xenopus tropicalis, transgenerational, Prediabetes, Metamorphosis, ComputingMilieux_MISCELLANEOUS, media_common, Multidisciplinary, [SDV.TOX.ECO] Life Sciences [q-bio]/Toxicology/Ecotoxicology, Insulin, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology.organism_classification, medicine.disease, 3. Good health, [SDE.BE] Environmental Sciences/Biodiversity and Ecology, 030104 developmental biology, Endocrinology, endocrine disruptors, [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, Metabolic syndrome, amphibian population decline, [SDE.BE]Environmental Sciences/Biodiversity and Ecology
Abstract

International audience; Despite numerous studies suggesting that amphibians are highly sensitive to endocrine disruptors (EDs), both their role in the decline of populations and the underlying mechanisms remain unclear. This study showed that frogs exposed throughout their life cycle to ED concentrations low enough to be considered safe for drinking water, developed a prediabetes phenotype and, more commonly, a metabolic syndrome. Female Xenopus tropicalis exposed from tadpole stage to benzo(a)pyrene or triclosan at concentrations of 50 ng⋅L-1 displayed glucose intolerance syndrome, liver steatosis, liver mitochondrial dysfunction, liver transcriptomic signature, and pancreatic insulin hypersecretion, all typical of a prediabetes state. This metabolic syndrome led to progeny whose metamorphosis was delayed and occurred while the individuals were both smaller and lighter, all factors that have been linked to reduced adult recruitment and likelihood of reproduction. We found that F1 animals did indeed have reduced reproductive success, demonstrating a lower fitness in ED-exposed Xenopus Moreover, after 1 year of depuration, Xenopus that had been exposed to benzo(a)pyrene still displayed hepatic disorders and a marked insulin secretory defect resulting in glucose intolerance. Our results demonstrate that amphibians are highly sensitive to EDs at concentrations well below the thresholds reported to induce stress in other vertebrates. This study introduces EDs as a possible key contributing factor to amphibian population decline through metabolism disruption. Overall, our results show that EDs cause metabolic disorders, which is in agreement with epidemiological studies suggesting that environmental EDs might be one of the principal causes of metabolic disease in humans.

Published
2018

5. Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury

Author

Karin Pernet-Gallay, Jean François Payen, Pierre Bouzat, Thibaut Trouve-Buisson, Anne Millet, Cécile Batandier, Lucie Gaide-Chevronnay, Eric Fontaine, Thierry Debillon, Emmanuel L. Barbier, INSERM U836, équipe 5, Neuroimagerie fonctionnelle et perfusion cérébrale, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Réanimation Pédiatrique, Hôpital Couple-Enfant-Hôpital Couple-Enfant, ANTE-INSERM U836, équipe 5, Neuroimagerie fonctionnelle et perfusion cérébrale, Pôle Anesthésie Réanimation, CHU Grenoble-Hôpital Michallon-CHU Grenoble-Hôpital Michallon, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Registre des Handicaps de l'Enfant et Observatoire Périnatal Isère, RHEOP, Centre Hospitalier Universitaire [Grenoble] (CHU), CIC - Grenoble, and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Anesthésie Réanimation

Subjects
0301 basic medicine, Male, Traumatic brain injury, [SDV]Life Sciences [q-bio], Pharmacology, Mitochondrion, Mitochondrial Membrane Transport Proteins, 03 medical and health sciences, Mitochondrial membrane transport protein, chemistry.chemical_compound, 0302 clinical medicine, Brain Injuries, Traumatic, Medicine, Animals, Humans, Rats, Wistar, Erythropoietin, ComputingMilieux_MISCELLANEOUS, Calcium metabolism, biology, business.industry, Mitochondrial Permeability Transition Pore, MPTP, medicine.disease, nervous system diseases, Mitochondria, Rats, 030104 developmental biology, Neuroprotective Agents, nervous system, Mitochondrial permeability transition pore, chemistry, Apoptosis, Anesthesia, biology.protein, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Inhibiting the opening of mitochondrial permeability transition pore (mPTP), thereby maintaining the mitochondrial membrane potential and calcium homeostasis, could reduce the induction of cell death. Although recombinant human erythropoietin (rhEpo) and carbamylated erythropoietin (Cepo) were shown to prevent apoptosis after traumatic brain injury (TBI), their impact on mPTP is yet unknown. Thirty minutes after diffuse TBI (impact-acceleration model), rats were intravenously administered a saline solution (TBI-saline), 5000 UI/kg rhEpo (TBI-rhEpo) or 50 μg/kg Cepo (TBI-Cepo). A fourth group received no TBI insult (sham-operated) (n = 11 rats per group). Post-traumatic brain edema was measured using magnetic resonance imaging. A first series of experiments was conducted 2 h after TBI (or equivalent) to investigate the mitochondrial function with the determination of thresholds for mPTP opening and ultrastructural mitochondrial changes. In addition, the intramitochondrial calcium content [Caim] was measured. In a second series of experiments, brain cell apoptosis was assessed at 24 h post-injury. TBI-rhEpo and TBI-Cepo groups had a reduced brain edema compared with TBI-saline. They had higher threshold for mPTP opening with succinate as substrate: 120 (120-150) (median, interquartiles) and 100 (100-120) versus 80 (60-90) nmol calcium/mg protein in TBI-saline, respectively (p 0.05). Similar findings were shown with glutamate-malate as substrate. TBI-rhEpo and Cepo groups had less morphological mitochondrial disruption in astrocytes. The elevation in [Caim] after TBI was not changed by rhEpo and Cepo treatment. Finally, rhEpo and Cepo reduced caspase-3 expression at 24 h post-injury. These results indicate that rhEpo and Cepo could modulate mitochondrial dysfunction after TBI. The mechanisms involved are discussed.

Published
2016

6. Middle Iron-Enriched Fructose Diet on Gestational Diabetes Risk and on Oxidative Stress in Offspring Rats

Author

Samar Rachidi, Mireille Osman, Josiane Arnaud, Cécile Batandier, Salam Zein, Karine Couturier, Isabelle Hininger-Favier, Anne-Sophie Gauchez, Farida Sitti, Clinical Pharmacy Department [Beirut, Lebanon], Lebanese University [Beirut] (LU), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Faculty of Medicine [Jakarta, Indonesia], Universitas Indonesia [Jakarta, Indonesia], Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire de Biologie Médicale [CHU Grenoble] (Plateforme de Radioactivité), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut de Biologie et de Pathologie - IBP [CHU Grenoble], We would like to thank the Rectorat of the Lebanese University, Beirut-Lebanon, to support this work., Dupuis, Christine, Universitas Indonesia (UI ), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP)

Subjects
Male, 0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Biochemistry, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, Medicine, Gestational diabetes, 2. Zero hunger, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Female, medicine.medical_specialty, Offspring, Iron, 030209 endocrinology & metabolism, Fructose, Hypoglycemia, Inorganic Chemistry, 03 medical and health sciences, Insulin resistance, Internal medicine, Animals, Rats, Wistar, Glycemic, business.industry, Insulin, Biochemistry (medical), nutritional and metabolic diseases, medicine.disease, High fructose diet, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Rats, Diabetes, Gestational, Disease Models, Animal, 030104 developmental biology, Endocrinology, chemistry, Oxidative stress, business
Abstract

International audience; Gestational diabetes mellitus (GDM) is associated with increased insulin resistance and a heightened level of oxidative stress (OS). Additionally, high iron consumption could also increase insulin resistance and OS, which could aggravate GDM risk. The aim of this study is to evaluate a high fructose diet (F) as an alternative experimental model of GDM on rats. We also have evaluated the worst effect of a fructose iron-enriched diet (FI) on glucose tolerance and OS status during pregnancy. Anthropometric parameters, plasma glucose levels, insulin, and lipid profile were assessed after delivery in rats fed an F diet. The effects observed in mothers (hyperglycemia, and hyperlipidemia) and on pups (macrosomia and hypoglycemia) are similar to those observed in women with GDM. Therefore, the fructose diet could be proposed as an experimental model of GDM. In this way, we can compare the effect of an iron-enriched diet on the metabolic and redox status of mother rats and their pups. The mothers' glycemic was similar in the F and FI groups, whereas the glycemic was significantly different in the newborn. In rat pups born to mothers fed on an FI diet, the activities of the antioxidant enzyme glutathione peroxidase (GPx) and glutathione-S-transferase in livers and GPx in brains were altered and the gender analysis showed significant differences. Thus, alterations in the glycemic and redox status in newborns suggest that fetuses are more sensitive than their mothers to the effect of an iron-enriched diet in the case of GDM pregnancy. This study proposed a novel experimental model for GDM and provided insights on the effect of a moderate iron intake in adding to the risk of glucose disorder and oxidative damage on newborns.

Published
2016

7. Cinnamon intake alleviates the combined effects of dietary-induced insulin resistance and acute stress on brain mitochondria

Author

Frédéric Canini, Cécile Batandier, Anne-Marie Roussel, Richard A. Anderson, Karine Couturier, Laurent Poulet, Isabelle Hininger, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Beltsville Human Nutrition Research Center, Institut de Recherche Biomédicale des Armées (IRBA), and ANR-07-PNRA-0003,CERVIRMIT,Cerveau, résistance à l'insuline et mitochondrie :Rôle neuroprotecteur des polyphénols de la cannelle dans un modèle animal de syndrome métabolique(2007)

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Antioxidant, Cinnamomum zeylanicum, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Biology, Mitochondrion, Biochemistry, p38 Mitogen-Activated Protein Kinases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin resistance, Internal medicine, medicine, Animals, Rats, Wistar, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Nutrition and Dietetics, Insulin, MPTP, Adenylate Kinase, Brain, Rotenone, medicine.disease, Mitochondria, Rats, Oxidative Stress, 030104 developmental biology, Endocrinology, chemistry, Mitochondrial permeability transition pore, Metabolic syndrome, Insulin Resistance, Reactive Oxygen Species, 030217 neurology & neurosurgery, Signal Transduction
Abstract

Insulin resistance (IR), which is a leading cause of the metabolic syndrome, results in early brain function alterations which may alter brain mitochondrial functioning. Previously, we demonstrated that rats fed a control diet and submitted to an acute restraint stress exhibited a delayed mitochondrial permeability transition pore (mPTP) opening. In this study, we evaluated the combined effects of dietary and emotional stressors as found in western way of life. We studied, in rats submitted or not to an acute stress, the effects of diet-induced IR on brain mitochondria, using a high fat/high fructose diet (HF(2)), as an IR inducer, with addition or not of cinnamon as an insulin sensitizer. We measured Ca(2+) retention capacity, respiration, ROS production, enzymatic activities and cell signaling activation. Under stress, HF(2) diet dramatically decreased the amount of Ca(2+) required to open the mPTP (13%) suggesting an adverse effect on mitochondrial survival. Cinnamon added to the diet corrected this negative effect and resulted in a partial recovery (30%). The effects related to cinnamon addition to the diet could be due to its antioxidant properties or to the observed modulation of PI3K-AKT-GSK3β and MAPK-P38 pathways or to a combination of both. These data suggest a protective effect of cinnamon on brain mitochondria against the negative impact of an HF(2) diet. Cinnamon could be beneficial to counteract deleterious dietary effects in stressed conditions.

Published
2016

8. Effects of a high-fat–high-fructose diet, stress and cinnamon on central expression of genes related to immune system, hypothalamic–pituitary–adrenocortical axis function and cerebral plasticity in rats – CORRIGENDUM

Author

Nathalie Marissal-Arvy, Cécile Batandier, Julien Dallennes, Frédéric Canini, Laurent Poulet, Karine Couturier, Isabelle Hininger-Favier, Marie-Pierre Moisan, Anne-Marie Roussel, Pierre Mormède, Nutrition et Neurobiologie intégrée, Institut National de la Recherche Agronomique (INRA), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Institut de Recherche Biomédicale des Armées, Département Neurosciences et Contraintes Opérationnelles, Unité de Neurophysiologie du Stress, 92123 Brétignysur- Orge cedex, France, Institut de Recherche Biomédicale des Armées, Département Neurosciences et Contraintes Opérationnelles, Unité de Neurophysiologie du Stress, Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT], ANR-07-PNRA-0003,CERVIRMIT,Cerveau, résistance à l'insuline et mitochondrie :Rôle neuroprotecteur des polyphénols de la cannelle dans un modèle animal de syndrome métabolique(2007), Nutrition et Neurobiologie intégrée (NutriNeuro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Nutrition and Dietetics, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), 030209 endocrinology & metabolism, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2014

9. Metyrapone effects on systemic and cerebral energy metabolism

Author

Nadine Fidier, André Peinnequin, Florence Fauvelle, Renaud Maury, Frédéric Canini, Antonia Alonso, Alain Buguet, Cécile Batandier, Jean-Baptiste Drouet, Raymond Cespuglio, Laurent Poulet, Département des environnements opérationnels (IRBA/CRSSA), Institut de Recherche Biomédicale des Armées (IRBA), Centre de Recherches du Service de Santé des Armées (CRSSA), Service de Santé des Armées, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Radiobiologie et Radiopathologie, Service de Santé des Armées-Ministère de la Défense, Département des Facteurs Humains, Radicaux libres, substrats énergétiques et physeopathologie cérébrale, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Radicaux Libres, Substrats Énergétiques et Physiopathologie Cérébrale, Institut de Recherche Biomédicale des Armées, Département Neurosciences et Contraintes Opérationnelles, Unité de Neurophysiologie du Stress, 92123 Brétignysur- Orge cedex, France, and Institut de Recherche Biomédicale des Armées, Département Neurosciences et Contraintes Opérationnelles, Unité de Neurophysiologie du Stress

Subjects
Male, medicine.medical_specialty, Transcription, Genetic, [SDV]Life Sciences [q-bio], AMP-Activated Protein Kinases, Biology, Hippocampus, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Prosencephalon, 0302 clinical medicine, Corticosterone, Internal medicine, medicine, Animals, Hippocampus (mythology), HSP70 Heat-Shock Proteins, RNA, Messenger, Enzyme Inhibitors, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, 0303 health sciences, Metyrapone, TOR Serine-Threonine Kinases, Glutamate receptor, Brain, AMPK, Hypothermia, Mitochondria, Rats, 3. Good health, Oxygen, Glutamine, Endocrinology, chemistry, medicine.symptom, Energy Metabolism, 030217 neurology & neurosurgery, Glucocorticoid, medicine.drug
Abstract

Metyrapone is a cytochrome P 450 inhibitor that protects against ischemia- and excitotoxicity-induced brain damages in rodents. This study examines whether metyrapone would act on energy metabolism in a manner congruent with its neuroprotective effect. In a first investigation, the rats instrumented with telemetric devices measuring abdominal temperature, received i.p. injection of either metyrapone or saline. One hour after injection, their blood and hippocampus were sampled. Hippocampus metabolite concentrations were measured using 1 H high-resolution magic angle spinning-magnetic resonance spectroscopy ( 1 H HRMAS-MRS). The hippocampus levels in phosphorylated mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) were measured by Western Blot analysis and those of c-fos and HSP70-2 mRNA were quantified by RT-PCR. In a second investigation, the rats received the same treatment and were sacrificed 1 h after. The functioning of mitochondria was immediately studied on their whole brain. Metyrapone provoked a slight hypothermia which was correlated to the increase in blood glucose concentration. Metyrapone also increased blood lactate concentrations without modifying hippocampus lactate content. In the hippocampus, metyrapone decreased γ-aminobutyric acid (GABA) and glutamate levels but increased glutamine and N-acetyl-aspartate contents (NAA). Phosphorylated mTOR and AMPK and the c-fos and HSP70-2 mRNA levels were similar between treatment groups. Metyrapone did not modify blood corticosterone levels. Mitochondrial oxygen consumption was similar in both groups whatever the substrate used. These metabolic modifications, which take place without modifying blood glucocorticoid levels, are consistent with the neuroprotective properties of metyrapone as demonstrated in animal models.

Published
2012

10. Erratum to: Prerequisites for ubiquinone analogs to prevent mitochondrial permeability transition-induced cell death

Author

Julie Belliere, Flavien Devun, Cécile Cottet-Rousselle, Cécile Batandier, Xavier Leverve, Eric Fontaine, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hamant, Sarah

Subjects
010404 medicinal & biomolecular chemistry, 010405 organic chemistry, Physiology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cell Biology, 01 natural sciences, ComputingMilieux_MISCELLANEOUS, 0104 chemical sciences
Abstract

International audience; N A

Published
2012

11. Cinnamon increases liver glycogen in an animal model of insulin resistance

Author

Xavier Leverve, Karine Couturier, Anne Marie Roussel, Richard A. Anderson, Frédéric Canini, Bolin Qin, Isabelle Hininger-Favier, Cécile Batandier, Manar Awada, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Integrity, Spring Hill, Diet, Genomics, and Immunology Laboratory, United States Department of Agriculture, Centre de Recherches du Service de Santé des Armées (CRSSA), Service de Santé des Armées, and Hamant, Sarah

Subjects
Male, medicine.medical_specialty, Cinnamomum zeylanicum, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Animal model, Insulin resistance, Internal medicine, Hfr cell, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Rats, Wistar, Glycogen synthase, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Messenger RNA, biology, Glycogen, Glucose transporter, medicine.disease, 3. Good health, Diet, Liver Glycogen, Rats, Insulin receptor, Disease Models, Animal, chemistry, Liver, biology.protein, Plant Preparations, Insulin Resistance, Energy Intake
Abstract

International audience; The objective of this study was to determine the effects of cinnamon on glycogen synthesis, related gene expression, and protein levels in the muscle and liver using an animal model of insulin resistance, the high-fat/high-fructose (HF/HFr) diet-fed rat. Four groups of 22 male Wistar rats were fed for 12 weeks with (1) HF/HFr diet to induce insulin resistance, (2) HF/HFr diet containing 20 g cinnamon per kilogram of diet, (3) control diet, and (4) control diet containing 20 g cinnamon per kilogram of diet. In the liver, cinnamon added to the HF/HFr diet led to highly significant increases of liver glycogen. There were no significant changes in animals consuming the control diet plus cinnamon. In the liver, cinnamon also counteracted the decreases of the gene expressions due to the consumption of the HF/HFr diet for the insulin receptor, insulin receptor substrates 1 and 2, glucose transporters 1 and 2, and glycogen synthase 1. In muscle, the decreased expressions of these genes by the HF/HFr diet and glucose transporter 4 were also reversed by cinnamon. In addition, the overexpression of glycogen synthase 3β messenger RNA levels and protein observed in the muscle of HF/HFr fed rats was decreased in animals consuming cinnamon. These data demonstrate that, in insulin-resistant rats, cinnamon improves insulin sensitivity and enhances liver glycogen via regulating insulin signaling and glycogen synthesis. Changes due to cinnamon in control animals with normal insulin sensitivity were not significant.

Published
2011

12. Cinnamon improves insulin sensitivity and alters the body composition in an animal model of the metabolic syndrome

Author

Xavier Leverve, Richard A. Anderson, Frédéric Canini, M. Awada, Cécile Batandier, Karine Couturier, Anne-Marie Roussel, Isabelle Hininger-Favier, Sinniger, Valérie, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches du Service de Santé des Armées (CRSSA), Service de Santé des Armées, Human Nutrition Research Center, and This work is a part of the CERVIRMIT study funded by the French National Agency for Research (PNRA 007) and is part of the Scientific Cooperative Convention Agreement (No. 58-123- 4N-F033 between the Human Nutrition Research Center (Beltsville, MD, USA) and the Joseph Fourier University (Grenoble, France).

Subjects
Male, Cinnamomum zeylanicum, 030309 nutrition & dietetics, medicine.medical_treatment, White adipose tissue, Biochemistry, Body composition, MESH: Glucose Clamp Technique, chemistry.chemical_compound, 0302 clinical medicine, MESH: Phenols, MESH: Metabolic Syndrome X, MESH: Animals, Metabolic Syndrome, 0303 health sciences, Cinnamon, Glucose clamp technique, 3. Good health, MESH: Insulin Resistance, MESH: Dietary Fats, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.medical_specialty, MESH: Rats, Biophysics, Blood sugar, 030209 endocrinology & metabolism, Fructose, Biology, 03 medical and health sciences, Insulin resistance, Phenols, In vivo, Internal medicine, MESH: Cinnamomum zeylanicum, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rats, Wistar, Molecular Biology, Flavonoids, MESH: Humans, Insulin, Polyphenols, MESH: Body Composition, MESH: Rats, Wistar, medicine.disease, Dietary Fats, MESH: Male, Rats, Disease Models, Animal, Endocrinology, chemistry, Glucose Clamp Technique, Metabolic syndrome, MESH: Disease Models, Animal, MESH: Flavonoids, MESH: Fructose
Abstract

International audience; Polyphenols from cinnamon (CN) have been described recently as insulin sensitizers and antioxidants but their effects on the glucose/insulin system in vivo have not been totally investigated. The aim of this study was to determine the effects of CN on insulin resistance and body composition, using an animal model of the metabolic syndrome, the high fat/high fructose (HF/HF) fed rat. Four groups of 22 male Wistar rats were fed for 12 weeks with: (i) (HF/HF) diet to induce insulin resistance, (ii) HF/HF diet containing 20 g cinnamon/kg of diet (HF/HF + CN), (iii) Control diet (C) and (iv) Control diet containing 20 g cinnamon/kg of diet (C + CN). Data from hyperinsulinemic euglycemic clamps showed a significant decrease of the glucose infusion rates in rats fed the HF/HF diet. Addition of cinnamon to the HF/HF diet increased the glucose infusion rates to those of the control rats. The HF/HF diet induced a reduction in pancreas weight which was prevented in HF/HF+CN group (p

Published
2010

13. New evidence of a mitochondrial genetic background paradox: Impact of the J haplogroup on the A3243G mutation

Author

Pascal Reynier, Benoit Arveiler, Agnès Rötig, Stéphane Allouche, Marc Crouzet, Rodrigue Rossignol, Cécile Batandier, Catherine Godinot, Marie-Laure Martin-Negrier, Pascal Murail, Delphine Feldmann, Christine Bellanne-Chantelot, Erwann Pennarun, Christophe Rocher, Patricia Amati-Bonneau, Didier Thoraval, Bénédicte Mousson de Camaret, Denis Pierron, Thierry Letellier, De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie (PACEA), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Physiopathologie mitochondriale, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Anatomie Pathologique, Centre hospitalier Universitaire, Biologie moléculaire et cellulaire de la signalisation (BMCS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Bioénergétique fondamentale et appliquée, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], 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 Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Génétique Humaine, Développement et Cancer, Université Bordeaux Segalen - Bordeaux 2, Department of Evolutionary Biology, Institute of Molecular and Cell Biology, Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], CHU Saint-Antoine [APHP], De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie ( PACEA ), Université de Bordeaux ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie moléculaire et cellulaire de la signalisation ( BMCS ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Handicaps génétiques de l'enfant ( Inserm U393 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de Cytogénétique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Institut de biochimie et génétique cellulaires ( IBGC ), and Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique ( CNRS )

Subjects
Haplogroup L4a, Mitochondrial DNA, lcsh:Internal medicine, Mitochondrial Diseases, RNA, Transfer, Leu, lcsh:QH426-470, [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Biology, pathogenic mutations, DNA, Mitochondrial, Polymorphism, Single Nucleotide, Haplogroup, White People, tRNALeu gene, Cohort Studies, 03 medical and health sciences, Negative selection, 0302 clinical medicine, Genetics, Humans, Genetics(clinical), lcsh:RC31-1245, Gene, Genetics (clinical), Phylogeny, 030304 developmental biology, pathogenic mitochondrial DNA, 0303 health sciences, Haplotype, DNA, 3. Good health, lcsh:Genetics, Haplotypes, [ SHS.ANTHRO-BIO ] Humanities and Social Sciences/Biological anthropology, Mutation, France, Restriction fragment length polymorphism, 030217 neurology & neurosurgery, Polymorphism, Restriction Fragment Length, Human mitochondrial DNA haplogroup, Research Article
Abstract

Background The A3243G mutation in the tRNALeu gene (UUR), is one of the most common pathogenic mitochondrial DNA (mtDNA) mutations in France, and is associated with highly variable and heterogeneous disease phenotypes. To define the relationships between the A3243G mutation and mtDNA backgrounds, we determined the haplogroup affiliation of 142 unrelated French patients – diagnosed as carriers of the A3243G mutation – by control-region sequencing and RFLP survey of their mtDNAs. Results The analysis revealed 111 different haplotypes encompassing all European haplogroups, indicating that the 3243 site might be a mutational hot spot. However, contrary to previous findings, we observed a statistically significant underepresentation of the A3243G mutation on haplogroup J in patients (p = 0.01, OR = 0.26, C.I. 95%: 0.08–0.83), suggesting that might be due to a strong negative selection at the embryo or germ line stages. Conclusion Thus, our study supports the existence of mutational hotspot on mtDNA and a "haplogroup J paradox," a haplogroup that may increase the expression of mtDNA pathogenic mutations, but also be beneficial in certain environmental contexts.

Published
2008

14. The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin

Author

Dominique Detaille, Michel Rigoulet, Eric Fontaine, Xavier Leverve, Bruno Guigas, Cécile Batandier, M-Yehia El-Mir, Bioénergétique fondamentale et appliquée, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departamento de Fisiologia y Farmacologia, Universidad de Salamanca, Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), and Hamant, Sarah

Subjects
MESH: Oxidation-Reduction, Physiology, Malates, Succinic Acid, Mitochondria, Liver, MESH: Malonates, Mitochondrion, MESH: Metformin, Membrane Potentials, chemistry.chemical_compound, 0302 clinical medicine, Adenosine Triphosphate, MESH: Adenosine Triphosphate, MESH: Animals, Phosphorylation, chemistry.chemical_classification, 0303 health sciences, MESH: Electron Transport Complex I, Respiratory chain complex, MESH: Reactive Oxygen Species, MESH: Glutamic Acid, Metformin, MESH: 2,4-Dinitrophenol, Malonate, Biochemistry, MESH: Mitochondria, Liver, Oxidation-Reduction, MESH: Rats, Glutamic Acid, Oxidative phosphorylation, Biology, In Vitro Techniques, Electron Transport, 03 medical and health sciences, Rotenone, MESH: Hypoglycemic Agents, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Hypoglycemic Agents, MESH: Membrane Potentials, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Rats, Wistar, MESH: Electron Transport, MESH: Malates, 030304 developmental biology, Reactive oxygen species, Electron Transport Complex I, MESH: Phosphorylation, Cell Biology, MESH: Rats, Wistar, Electron transport chain, Malonates, Rats, MESH: Succinic Acid, chemistry, NAD+ kinase, 2,4-Dinitrophenol, Reactive Oxygen Species, MESH: Rotenone, 030217 neurology & neurosurgery
Abstract

International audience; Mitochondrial reactive oxygen species (ROS) production was investigated in mitochondria extracted from liver of rats treated with or without metformin, a mild inhibitor of respiratory chain complex 1 used in type 2 diabetes. A high rate of ROS production, fully suppressed by rotenone, was evidenced in non-phosphorylating mitochondria in the presence of succinate as a single complex 2 substrate. This ROS production was substantially lowered by metformin pretreatment and by any decrease in membrane potential (Delta Phi(m)), redox potential (NADH/NAD), or phosphate potential, as induced by malonate, 2,4-dinitrophenol, or ATP synthesis, respectively. ROS production in the presence of glutamate-malate plus succinate was lower than in the presence of succinate alone, but higher than in the presence of glutamate-malate. Moreover, while rotenone both increased and decreased ROS production at complex 1 depending on forward (glutamate-malate) or reverse (succinate) electron flux, no ROS overproduction was evidenced in the forward direction with metformin. Therefore, we propose that reverse electron flux through complex 1 is an alternative pathway, which leads to a specific metformin-sensitive ROS production.

Published
2006

15. Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process

Author

Cécile Batandier, Christiane Chauvin, Nicolas Wiernsperger, Dominique Detaille, Eric Fontaine, Xavier Leverve, Bruno Guigas, Bioénergétique fondamentale et appliquée, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Merck-Santé, Merck & Co. Inc, and Hamant, Sarah

Subjects
MESH: Cell Death, medicine.medical_specialty, Programmed cell death, animal structures, MESH: Mitochondria, Endocrinology, Diabetes and Metabolism, Biology, Mitochondrion, medicine.disease_cause, MESH: Metformin, environment and public health, Permeability, Cell Line, 03 medical and health sciences, 0302 clinical medicine, MESH: Skin, Internal medicine, Cyclosporin a, MESH: Microcirculation, Internal Medicine, medicine, Humans, 030304 developmental biology, Skin, 0303 health sciences, MESH: Humans, Cell Death, Microcirculation, Metformin, 3. Good health, Mitochondria, MESH: Cell Line, Endothelial stem cell, MESH: Glucose, enzymes and coenzymes (carbohydrates), Endocrinology, Glucose, Mitochondrial permeability transition pore, Apoptosis, 030220 oncology & carcinogenesis, MESH: Permeability, Endothelium, Vascular, MESH: Endothelium, Vascular, Oxidative stress, medicine.drug
Abstract

International audience; Hyperglycemia-induced oxidative stress is detrimental for endothelial cells, contributing to the vascular complications of diabetes. The mitochondrial permeability transition pore (PTP) is an oxidative stress-sensitive channel involved in cell death; therefore, we have examined its potential role in endothelial cells exposed to oxidative stress or high glucose level. Metformin, an antihyperglycemic agent used in type 2 diabetes, was also investigated because it inhibits PTP opening in transformed cell lines. Cyclosporin A (CsA), the reference PTP inhibitor, and a therapeutic dose of metformin (100 micromol/l) led to PTP inhibition in permeabilized human microvascular endothelial cells (HMEC-1). Furthermore, exposure of intact HMEC-1 or primary endothelial cells from either human umbilical vein or bovine aorta to the oxidizing agent tert-butylhydroperoxide or to 30 mmol/l glucose triggered PTP opening, cytochrome c decompartmentalization, and cell death. CsA or metformin prevented all of these effects. The antioxidant N-acetyl-l-cysteine also prevented hyperglycemia-induced apoptosis. We conclude that 1) elevated glucose concentration leads to an oxidative stress that favors PTP opening and subsequent cell death in several endothelial cell types and 2) metformin prevents this PTP opening-related cell death. We propose that metformin improves diabetes-associated vascular disease both by lowering blood glucose and by its effect on PTP regulation.

Published
2005

16. Fat intake reverses the beneficial effects of low caloric intake on skeletal muscle mitochondrial H(2)O(2) production

Author

Brigitte Sibille, Xavier Leverve, Roland Favier, Dominique Letexier, Blandine Garait, Cécile Batandier, Jean-Louis Rouanet, Benjamin Rey, Stéphane Servais, David Perrin, Karine Couturier, Hamant, Sarah, Bioénergétique fondamentale et appliquée, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie intégrative, cellulaire et moléculaire (PICM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
Male, Thyroid Gland, MESH: Energy Intake, Mitochondrion, medicine.disease_cause, Biochemistry, Oxygen, Ion Channels, chemistry.chemical_compound, 0302 clinical medicine, Uncoupling Protein 3, MESH: Animals, MESH: Oxygen Consumption, Hydrogen peroxide, chemistry.chemical_classification, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Energy Metabolism, MESH: Mitochondria, Muscle, MESH: Mitochondrial Proteins, MESH: Reactive Oxygen Species, MESH: Motor Activity, Mitochondria, medicine.anatomical_structure, MESH: Dietary Fats, MESH: Hydrogen Peroxide, MESH: Electron Transport Chain Complex Proteins, medicine.medical_specialty, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], MESH: Rats, chemistry.chemical_element, MESH: Carrier Proteins, Motor Activity, Mitochondrial Proteins, 03 medical and health sciences, Oxygen Consumption, Oxidoreductase, Physiology (medical), Internal medicine, medicine, Animals, Rats, Wistar, Muscle, Skeletal, Caloric Restriction, 030304 developmental biology, Reactive oxygen species, MESH: Caloric Restriction, Body Weight, Skeletal muscle, Hydrogen Peroxide, Metabolism, MESH: Rats, Wistar, Dietary Fats, MESH: Male, Mitochondria, Muscle, Rats, MESH: Body Weight, MESH: Thyroid Gland, Endocrinology, Electron Transport Chain Complex Proteins, chemistry, MESH: Ion Channels, Carrier Proteins, Energy Intake, Energy Metabolism, Reactive Oxygen Species, metabolism, 030217 neurology & neurosurgery, Oxidative stress
Abstract

International audience; Food restriction is the most effective modulator of oxidative stress and it is believed that a reduction in caloric intake per se is responsible for the reduced generation of reactive oxygen species (ROS) by mitochondria. Hydrogen peroxide (H(2)O(2)) generation and oxygen consumption (O(2)) by skeletal muscle mitochondria were determined in a peculiar strain of rats (Lou/C) characterized by a self-low-caloric intake and a dietary preference for fat. These rats were fed either with a standard high-carbohydrate (HC) or a high-fat (HF) diet and the results were compared to those measured in Wistar rats fed a HC diet. H(2)O(2) production was significantly reduced in Lou/C rats fed a HC diet; this effect was not due to a lower O(2) consumption but rather to a decrease in rotenone-sensitive NADH-ubiquinone oxidoreductase activity and increased expression of uncoupling proteins 2 and 3. The reduced H(2)O(2) generation displayed by Lou/C rats was accompanied by a significant inhibition of permeability transition pore (PTP) opening. H(2)O(2) production was restored and PTP inhibition was relieved when Lou/C rats were allowed to eat a HF diet, suggesting that the reduced oxidative stress provided by low caloric intake is lost when fat proportion in the diet is increased.

Published
2005

17. Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study

Author

Christiane Chauvin, Cécile Batandier, Dominique Detaille, Xavier Leverve, Eric Fontaine, Frédéric De Oliveira, Bruno Guigas, Bioénergétique fondamentale et appliquée, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hamant, Sarah

Subjects
MESH: Cell Death, MESH: Metformin, Biochemistry, Mitochondrial Membrane Transport Proteins, Ion Channels, KB Cells, chemistry.chemical_compound, 0302 clinical medicine, Cyclosporin a, oxidative stress, MESH: Oxygen Consumption, 0303 health sciences, MESH: Electron Transport Complex I, Cytochrome c, Respiratory chain complex, digestive, oral, and skin physiology, Cytochromes c, MESH: Mitochondrial Membrane Transport Proteins, MESH: Cytochromes c, Metformin, mitochondria, MESH: Intracellular Membranes, cell death, MESH: Permeability, MESH: Citrate (si)-Synthase, medicine.drug, Research Article, medicine.medical_specialty, Programmed cell death, MESH: Mitochondria, MESH: KB Cells, Citrate (si)-Synthase, Biology, complex 1, Permeability, 03 medical and health sciences, Oxygen Consumption, Internal medicine, MESH: Hypoglycemic Agents, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Hypoglycemic Agents, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Propidium iodide, Molecular Biology, permeability transition pore (PTP), 030304 developmental biology, Electron Transport Complex I, MESH: Humans, Mitochondrial Permeability Transition Pore, Cell Biology, Intracellular Membranes, Endocrinology, chemistry, Mitochondrial permeability transition pore, Cell culture, MESH: Ion Channels, biology.protein, metformin, 030217 neurology & neurosurgery
Abstract

International audience; Metformin, a drug widely used in the treatment of Type II diabetes, has recently received attention owing to new findings regarding its mitochondrial and cellular effects. In the present study, the effects of metformin on respiration, complex 1 activity, mitochondrial permeability transition, cytochrome c release and cell death were investigated in cultured cells from a human carcinoma-derived cell line (KB cells). Metformin significantly decreased respiration both in intact cells and after permeabilization. This was due to a mild and specific inhibition of the respiratory chain complex 1. In addition, metformin prevented to a significant extent mitochondrial permeability transition both in permeabilized cells, as induced by calcium, and in intact cells, as induced by the glutathione-oxidizing agent t-butyl hydroperoxide. This effect was equivalent to that of cyclosporin A, the reference inhibitor. Finally, metformin impaired the t-butyl hydroperoxide-induced cell death, as judged by Trypan Blue exclusion, propidium iodide staining and cytochrome c release. We propose that metformin prevents the permeability transition-related commitment to cell death in relation to its mild inhibitory effect on complex 1, which is responsible for a decreased probability of mitochondrial permeability transition.

Published
2004

18. How valid is the concept of antioxidants and cell injury?

Author

Xavier Leverve, Cécile Batandier, Eric Fontaine, Hamant, Sarah, Bioénergétique fondamentale et appliquée, and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Pathology, medicine.medical_specialty, Cells, Respiratory chain, 030204 cardiovascular system & hematology, Bioinformatics, Antioxidants, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Medicine, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, MESH: Cells, 0303 health sciences, Reactive oxygen species, MESH: Humans, MESH: Oxidative Stress, business.industry, MESH: Antioxidants, Cell injury, MESH: Reactive Oxygen Species, Oxidative Stress, chemistry, Reactive Oxygen Species, business
Abstract

International audience

Published
2002

19. Determination of mitochondrial reactive oxygen species: methodological aspects

Author

Xavier Leverve, Eric Fontaine, Christiane Keriel, Cécile Batandier, Hamant, Sarah, Bioénergétique fondamentale et appliquée, and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Mitochondria, Energy metabolism, Oxidative phosphorylation, Computational biology, Review, Mitochondrion, Biology, medicine.disease_cause, Models, Biological, Antioxidants, Electron Transport, 03 medical and health sciences, 0302 clinical medicine, Bias, MESH: Analysis of Variance, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Fluorometry, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Electron Transport, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Reactive oxygen species, Analysis of Variance, MESH: Oxidative Stress, MESH: Spectrophotometry, MESH: Antioxidants, MESH: Fluorometry, MESH: Models, Biological, MESH: Reactive Oxygen Species, Cell Biology, MESH: Bias (Epidemiology), Redox status, Mitochondria, Oxidative Stress, chemistry, Biochemistry, Spectrophotometry, 030220 oncology & carcinogenesis, Molecular Medicine, Reactive Oxygen Species, Oxidative stress
Abstract

International audience; The generation of Reactive Oxygen Species (ROS) as by-products in mitochondria Electron Transport Chain (ETC) has long been admitted as the cost of aerobic energy metabolism with oxidative damages as consequence. The purpose of this methodological review is to present some of the most widespread methods of ROS generation and to underline the limitations as well as some problems, identified with some experiments as examples, in the interpretation of such results. There is now no doubt that besides their pejorative role, ROS are involved in a variety of cellular processes for the continuous adaptation of the cell to its environment. Because ROS metabolism is a complex area (low production, instability of species, efficient antioxidant defense system, several places of production...) bias, variances and limitations in ROS measurements must be recognized in order to avoid artefactual conclusions, and especially to improve our understanding of physiological and pathophysiological mechanisms of such phenomenon.

Published
2002

20. The ROS Production Induced by a Reverse-Electron Flux at Respiratory-Chain Complex 1 is Hampered by Metformin.

Author

Cécile Batandier, Bruno Guigas, Dominique Detaille, M. El-Mir, Eric Fontaine, M. Rigoulet, and X. Leverve

Abstract

Mitochondrial reactive oxygen species (ROS) production was investigated in mitochondria extracted from liver of rats treated with or without metformin, a mild inhibitor of respiratory chain complex 1 used in type 2 diabetes. A high rate of ROS production, fully suppressed by rotenone, was evidenced in non-phosphorylating mitochondria in the presence of succinate as a single complex 2 substrate. This ROS production was substantially lowered by metformin pretreatment and by any decrease in membrane potential (Δ < eqid1 > m), redox potential (NADH/NAD), or phosphate potential, as induced by malonate, 2,4-dinitrophenol, or ATP synthesis, respectively. ROS production in the presence of glutamate–malate plus succinate was lower than in the presence of succinate alone, but higher than in the presence of glutamate–malate. Moreover, while rotenone both increased and decreased ROS production at complex 1 depending on forward (glutamate–malate) or reverse (succinate) electron flux, no ROS overproduction was evidenced in the forward direction with metformin. Therefore, we propose that reverse electron flux through complex 1 is an alternative pathway, which leads to a specific metformin-sensitive ROS production. [ABSTRACT FROM AUTHOR]

Published
2006

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