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1. Insulin resistance per se drives early and reversible dysbiosis-mediated gut barrier impairment and bactericidal dysfunction

Author

Dalale Gueddouri, Michèle Caüzac, Véronique Fauveau, Fadila Benhamed, Wafa Charifi, Lucie Beaudoin, Matthieu Rouland, Florian Sicherre, Agnès Lehuen, Catherine Postic, Gaëlle Boudry, Anne-Françoise Burnol, and Sandra Guilmeau

Subjects
Insulin resistance, Gut barrier, Dysbiosis, Antimicrobial defenses, Internal medicine, RC31-1245
Abstract

Objective: A common feature of metabolic diseases is their association with chronic low-grade inflammation. While enhanced gut permeability and systemic bacterial endotoxin translocation have been suggested as key players of this metaflammation, the mechanistic bases underlying these features upon the diabesity cascade remain partly understood. Methods: Here, we show in mice that, independently of obesity, the induction of acute and global insulin resistance and associated hyperglycemia, upon treatment with an insulin receptor (IR) antagonist (S961), elicits gut hyperpermeability without triggering systemic inflammatory response. Results: Of note, S961-treated diabetic mice display major defects of gut barrier epithelial functions, such as increased epithelial paracellular permeability and impaired cell-cell junction integrity. We also observed in these mice the early onset of a severe gut dysbiosis, as characterized by the bloom of pro-inflammatory Proteobacteria, and the later collapse of Paneth cells antimicrobial defense. Interestingly, S961 treatment discontinuation is sufficient to promptly restore both the gut microbial balance and the intestinal barrier integrity. Moreover, fecal transplant approaches further confirm that S961-mediated dybiosis contributes at least partly to the disruption of the gut selective epithelial permeability upon diabetic states. Conclusions: Together, our results highlight that insulin signaling is an indispensable gatekeeper of intestinal barrier integrity, acting as a safeguard against microbial imbalance and acute infections by enteropathogens.

Published
2022
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2. Dual regulation of TxNIP by ChREBP and FoxO1 in liver

Author

Benedicte Noblet, Fadila Benhamed, InSug O-Sullivan, Wenwei Zhang, Gaëlle Filhoulaud, Alexandra Montagner, Arnaud Polizzi, Solenne Marmier, Anne-Françoise Burnol, Sandra Guilmeau, Tarik Issad, Hervé Guillou, Catherine Bernard, Terry Unterman, and Catherine Postic

Subjects
Molecular Physiology, Molecular Biology, Endocrinology, Science
Abstract

Summary: TxNIP (Thioredoxin-interacting protein) is considered as a potential drug target for type 2 diabetes. Although TxNIP expression is correlated with hyperglycemia and glucotoxicity in pancreatic β cells, its regulation in liver cells has been less investigated. In the current study, we aim at providing a better understanding of Txnip regulation in hepatocytes in response to physiological stimuli and in the context of hyperglycemia in db/db mice. We focused on regulatory pathways governed by ChREBP (Carbohydrate Responsive Element Binding Protein) and FoxO1 (Forkhead box protein O1), transcription factors that play central roles in mediating the effects of glucose and fasting on gene expression, respectively. Studies using genetically modified mice reveal that hepatic TxNIP is up-regulated by both ChREBP and FoxO1 in liver cells and that its expression strongly correlates with fasting, suggesting a major role for this protein in the physiological adaptation to nutrient restriction.

Published
2021
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3. A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response

Author

Alison Iroz, Alexandra Montagner, Fadila Benhamed, Françoise Levavasseur, Arnaud Polizzi, Elodie Anthony, Marion Régnier, Edwin Fouché, Céline Lukowicz, Michèle Cauzac, Emilie Tournier, Marcio Do-Cruzeiro, Martine Daujat-Chavanieu, Sabine Gerbal-Chalouin, Véronique Fauveau, Solenne Marmier, Anne-Françoise Burnol, Sandra Guilmeau, Yannick Lippi, Jean Girard, Walter Wahli, Renaud Dentin, Hervé Guillou, and Catherine Postic

Subjects
Biology (General), QH301-705.5
Abstract

Summary: While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp−/− mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp−/− mice. Unexpectedly, carbohydrate challenge of hepatic Pparα knockout mice also demonstrated a PPARα-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21. : FGF21 is a hepatokine with beneficial metabolic effects, including control of sucrose preference. Iroz et al. demonstrate that Fgf21 is a unique hepatic gene inducible by both fasting and glucose signals and that the transcription factors PPARα and ChREBP both regulate the endocrine control of sugar intake by hepatic FGF21. Keywords: ChREBP, PPARα, FGF21, glucose intake, sucrose preference

Published
2017
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4. O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic β Cells

Author

Gaelle Filhoulaud, Fadila Benhamed, Patrick Pagesy, Caroline Bonner, Yann Fardini, Anissa Ilias, Jamileh Movassat, Anne-Françoise Burnol, Sandra Guilmeau, Julie Kerr-Conte, François Pattou, Tarik Issad, and Catherine Postic

Subjects
O-GlcNAcylation, TXNIP (thioredoxin-interacting protein), pancreatic beta cells, hyperglycemia, inflammasome, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Thioredoxin interacting protein (TxNIP), which strongly responds to glucose, has emerged as a central mediator of glucotoxicity in pancreatic β cells. TxNIP is a scaffold protein interacting with target proteins to inhibit or stimulate their activity. Recent studies reported that high glucose stimulates the interaction of TxNIP with the inflammasome protein NLRP3 (NLR family, pyrin domain containing 3) to increase interleukin-1 β (IL1β) secretion by pancreatic β cells. To better understand the regulation of TxNIP by glucose in pancreatic β cells, we investigated the implication of O-linked β-N-acetylglucosamine (O-GlcNAcylation) in regulating TxNIP at the posttranslational level. O-GlcNAcylation of proteins is controlled by two enzymes: the O-GlcNAc transferase (OGT), which transfers a monosaccharide to serine/threonine residues on target proteins, and the O-GlcNAcase (OGA), which removes it. Our study shows that TxNIP is subjected to O-GlcNAcylation in response to high glucose concentrations in β cell lines. Modification of the O-GlcNAcylation pathway through manipulation of OGT or OGA expression or activity significantly modulates TxNIP O-GlcNAcylation in INS1 832/13 cells. Interestingly, expression and O-GlcNAcylation of TxNIP appeared to be increased in islets of diabetic rodents. At the mechanistic level, the induction of the O-GlcNAcylation pathway in human and rat islets promotes inflammasome activation as evidenced by enhanced cleaved IL1β. Overexpression of OGT in HEK293 or INS1 832/13 cells stimulates TxNIP and NLRP3 interaction, while reducing TxNIP O-GlcNAcylation through OGA overexpression destabilizes this interaction. Altogether, our study reveals that O-GlcNAcylation represents an important regulatory mechanism for TxNIP activity in β cells.

Published
2019
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5. Dual regulation of TxNIP by ChREBP and FoxO1 in liver

Author

Tarik Issad, Anne-Françoise Burnol, Catherine Bernard, Gaëlle Filhoulaud, Sandra Guilmeau, InSug O-Sullivan, Arnaud Polizzi, Bénédicte Noblet, Alexandra Montagner, Catherine Postic, Hervé Guillou, Fadila Benhamed, Solenne Marmier, Wenwei Zhang, Terry G. Unterman, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Illinois [Chicago] (UIC), University of Illinois System, Jesse Brown Veterans Affairs Medical Center, ToxAlim (ToxAlim), 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-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Postic's lab (U1016-Institut Cochin) is supported by grants from Servier Laboratories , FRM (Foundation for the Medical Research, DEQ20150331744 ), EFSD -Novonordisk (European Foundation for the Study of Diabetes), and National Agency for Research (ANR) ( ANR-15-CE14-0026- Hepatokind). Unterman's lab is supported by VA Merit Review Grant ( IO1BX001968 )., ANR-15-CE14-0026,Hepatokind,FGF21 contrôle homéostasie glucidique via les facteurs de transcription ChREBP et PPARa(2015), LESUR, Hélène, FGF21 contrôle homéostasie glucidique via les facteurs de transcription ChREBP et PPARa - - Hepatokind2015 - ANR-15-CE14-0026 - AAPG2015 - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], FOXO1, Context (language use), 02 engineering and technology, Type 2 diabetes, Biology, Article, Molecular Physiology, 03 medical and health sciences, Endocrinology, Gene expression, medicine, Carbohydrate-responsive element-binding protein, lcsh:Science, Transcription factor, Molecular Biology, Multidisciplinary, 021001 nanoscience & nanotechnology, medicine.disease, 3. Good health, Cell biology, Genetically modified organism, [SDV] Life Sciences [q-bio], [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, 030104 developmental biology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, lcsh:Q, 0210 nano-technology, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, TXNIP
Abstract

Summary TxNIP (Thioredoxin-interacting protein) is considered as a potential drug target for type 2 diabetes. Although TxNIP expression is correlated with hyperglycemia and glucotoxicity in pancreatic β cells, its regulation in liver cells has been less investigated. In the current study, we aim at providing a better understanding of Txnip regulation in hepatocytes in response to physiological stimuli and in the context of hyperglycemia in db/db mice. We focused on regulatory pathways governed by ChREBP (Carbohydrate Responsive Element Binding Protein) and FoxO1 (Forkhead box protein O1), transcription factors that play central roles in mediating the effects of glucose and fasting on gene expression, respectively. Studies using genetically modified mice reveal that hepatic TxNIP is up-regulated by both ChREBP and FoxO1 in liver cells and that its expression strongly correlates with fasting, suggesting a major role for this protein in the physiological adaptation to nutrient restriction., Graphical abstract, Highlights • TxNIP is considered as a potential candidate drug target for type 2 diabetes • We provide better understanding of Txnip regulation and function in liver • Hepatic Txnip is up-regulated by both ChREBP and FoxO1 transcription factors • We suggest a role for TxNIP in the physiological adaptation to nutrient restriction, Molecular Physiology ; Molecular Biology ; Endocrinology

Published
2021
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6. Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia

Author

Philippe J. Sansonetti, Matthieu Rouland, Maria Rescigno, Lucie Cagninacci, Nathalie Vergnolle, Sandra Guilmeau, Juliette Mouriès, Latif Rachdi, Lucie Beaudoin, Azadeh Saffarian, Agnès Lehuen, Dalale Gueddouri, Anne-Françoise Burnol, Ute Christine Rogner, Asmaa Tazi, Ophélie Rouxel, Léo Bertrand, Thierry Pedron, Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Pathogénie microbienne moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humanitas University [Milan] (Hunimed), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), LabEx Inflamex, This work was supported by Agence Nationale de la Recherche (ANR-11-IDEX-0005-02 Laboratory of Excellence INFLAMEX and ANR-17-CE14-0002-01 Diab1MAIT), Fondation pour la Recherche Médicale (DEQ20140329520 and EQU201903007779), the INSERM crosscutting program on microbiota and the European Foundation for the Study of Diabetes–Juvenile Diabetes Research Foundation–MR, OR and LBer were supported by the French Ministry of Research., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-17-CE14-0002,Diab1MAIT,Rôle des cellules MAIT dans le diabète de type 1 chez l'homme et la souris(2017), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Fondation pour la Recherche Medicale (DEQ20140329520 and EQU201903007779), European Foundation for the Study of Diabetes-Juvenile Diabetes Research Foundation-MR, OR and LBer are supported by the French Ministry of Research, and the INSERM crosscutting program on microbiota is supported by the French Ministry of Research

Subjects
0301 basic medicine, endocrine system diseases, medicine.medical_treatment, Segmented filamentous bacteria, intestinal microbiology, Inflammation, Gut flora, digestive system, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Diabetes Mellitus, medicine, Animals, Intestinal Mucosa, Autoimmune disease, Bacteria, biology, Insulin, digestive, oral, and skin physiology, Gastroenterology, Interleukin, Epithelial Cells, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gastrointestinal Microbiome, 3. Good health, Disease Models, Animal, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Diabetes Mellitus, Type 1, 030104 developmental biology, Hyperglycemia, 030220 oncology & carcinogenesis, Immunology, mucosal immunity, Cytokines, Dysbiosis, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

ObjectiveType 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β-cells producing insulin. Both T1D patients and animal models exhibit gut microbiota and mucosa alterations, although the exact cause for these remains poorly understood. We investigated the production of key cytokines controlling gut integrity, the abundance of segmented filamentous bacteria (SFB) involved in the production of these cytokines, and the respective role of autoimmune inflammation and hyperglycaemia.DesignWe used several mouse models of autoimmune T1D as well as mice rendered hyperglycaemic without inflammation to study gut mucosa and microbiota dysbiosis. We analysed cytokine expression in immune cells, epithelial cell function, SFB abundance and microbiota composition by 16S sequencing. We assessed the role of anti-tumour necrosis factor α on gut mucosa inflammation and T1D onset.ResultsWe show in models of autoimmune T1D a conserved loss of interleukin (IL)-17A, IL-22 and IL-23A in gut mucosa. Intestinal epithelial cell function was altered and gut integrity was impaired. These defects were associated with dysbiosis including progressive loss of SFB. Transfer of diabetogenic T-cells recapitulated these gut alterations, whereas induction of hyperglycaemia with no inflammation failed to do so. Moreover, anti-inflammatory treatment restored gut mucosa and immune cell function and dampened diabetes incidence.ConclusionOur results demonstrate that gut mucosa alterations and dysbiosis in T1D are primarily linked to inflammation rather than hyperglycaemia. Anti-inflammatory treatment preserves gut homeostasis and protective commensal flora reducing T1D incidence.

Published
2021
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7. Identification of insulin-sensitizing molecules acting by disrupting the interaction between the Insulin Receptor and Grb14

Author

Anaïs, Gondoin, Cornelia, Hampe, Richard, Eudes, Cyril, Fayolle, Cécile, Pierre-Eugène, Maria, Miteva, Bruno O, Villoutreix, Florence, Charnay-Pouget, David J, Aitken, Tarik, Issad, Anne-Françoise, Burnol, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Molécules Thérapeutiques in silico (MTI), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), ANR-06-PHYS-0014,Grb14,Contrôle de la sensibilité à l'insuline du tissu adipeux par la protéine Grb14 : conséquences physiologiques d'une modulation de l'expression de Grb14, et développement d'agents insulino-sensibilisateurs inhibant l'interaction Grb14/récepteur(2006), CHARNAY-POUGET, Florence, and Physiopathologie des maladies humaines (Physio) - Contrôle de la sensibilité à l'insuline du tissu adipeux par la protéine Grb14 : conséquences physiologiques d'une modulation de l'expression de Grb14, et développement d'agents insulino-sensibilisateurs inhibant l'interaction Grb14/récepteur - - Grb142006 - ANR-06-PHYS-0014 - PHYSIO - VALID

Subjects
Cell Survival, [SDV]Life Sciences [q-bio], lcsh:Medicine, Article, [PHYS] Physics [physics], Phosphatidylinositol 3-Kinases, Sulfanilamides, [CHIM] Chemical Sciences, Fluorescence Resonance Energy Transfer, Humans, Insulin, [CHIM]Chemical Sciences, Phosphorylation, lcsh:Science, Adaptor Proteins, Signal Transducing, [PHYS]Physics [physics], Binding Sites, lcsh:R, Receptor, Insulin, Protein Structure, Tertiary, Molecular Docking Simulation, [SDV] Life Sciences [q-bio], HEK293 Cells, lcsh:Q, Protein Binding, Signal Transduction
Abstract

International audience; Abstract Metabolic diseases are characterized by a decreased action of insulin. During the course of the disease, usual treatments frequently fail and patients are finally submitted to insulinotherapy. There is thus a need for innovative therapeutic strategies to improve insulin action. Growth factor receptor-bound protein 14 (Grb14) is a molecular adapter that specifically binds to the activated insulin receptor (IR) and inhibits its tyrosine kinase activity. Molecules disrupting Grb14-IR binding are therefore potential insulin-sensitizing agents. We used Structure-Based Virtual Ligand Screening to generate a list of 1000 molecules predicted to hinder Grb14-IR binding. Using an acellular bioluminescence resonance energy transfer (BRET) assay, we identified, out of these 1000 molecules, 3 compounds that inhibited Grb14-IR interaction. Their inhibitory effect on insulin-induced Grb14-IR interaction was confirmed in co-immunoprecipitation experiments. The more efficient molecule (C8) was further characterized. C8 increased downstream Ras-Raf and PI3-kinase insulin signaling, as shown by BRET experiments in living cells. Moreover, C8 regulated the expression of insulin target genes in mouse primary hepatocytes. These results indicate that C8, by reducing Grb14-IR interaction, increases insulin signalling. The use of C8 as a lead compound should allow for the development of new molecules of potential therapeutic interest for the treatment of diabetes.

Published
2017
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8. Regulation of hepatokine gene expression in response to fasting and feeding: Influence of PPARa and insulin-dependent signaling in hepatocytes

Author

Pierre Gourdy, Arnaud Polizzi, Frédéric Lasserre, Walter Wahli, Maeva Guillaume, Marion Régnier, Blandine Tramunt, Sarra Smati, Céline Lukowicz, Catherine Postic, Hervé Guillou, Anne-Françoise Burnol, Alexandra Montagner, Tiffany Fougeray, Anne Fougerat, ToxAlim (ToxAlim), 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-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Nanyang Technological University [Singapour], Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Service de Diabétologie - Maladies Métaboliques - Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Institut National de la Sante et de la Recherche Medicale (Inserm), Societe francophone du diabete, Societe francaise de nutrition, Nanyang Technological University, French National Research Agency (ANR), Region Occitanie, ANR-15-CE14-0026,Hepatokind,FGF21 contrôle homéostasie glucidique via les facteurs de transcription ChREBP et PPARa(2015), NXP Semiconductors, Laboratoire de météorologie physique (LaMP), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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), Université Laval, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Integrative Genomics, Université de Lausanne (UNIL), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-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 National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Lee Kong Chian School of Medicine (LKCMedicine)

Subjects
Nutritional regulation, medicine.medical_specialty, FGF21, Insulin Receptor, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Gene Expression, Peroxisome proliferator-activated receptor, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Eating, Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, ANGPTL4, Internal medicine, Gene expression, Internal Medicine, medicine, Angiopoietin-Like Protein 4, Animals, Insulin, Medicine [Science], PPAR alpha, IGFBP1, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, PPAR-alpha, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, chemistry.chemical_classification, biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Fasting, General Medicine, Receptor, Insulin, Fibroblast Growth Factors, Insulin receptor, chemistry, Hepatocytes, biology.protein, GDF15, Hepatokines, Signal Transduction, Follistatin
Abstract

Aim – In hepatocytes, the peroxisome proliferator-activated receptor (PPAR)-a and insulin receptor (IR) are critical for transcriptional responses to fasting and feeding, respectively. The present report analyzes the effects of nutritional status (fasting vs feeding) on the expression of a large panel of hepatokines in hepatocyte-specific PPAR-a (Ppara hep/) and IR (IRhep/) null mice. Methods – Pparahep/ and IRhep/ mice, and their wild-type littermates, were subjected to fasting or feeding metabolic challenges, then analyzed for hepatokine gene expression. Experiments were conducted in mice of both genders. Results – Our data confirmed that PPAR-a is essential for regulating fasting-induced Fgf21 and Angptl4 expression. In mice lacking PPAR-a, fasting led to increased Igfbp1 and Gdf15 gene expression. In the absence of hepatic IR, feeding induced overexpression of Igfbp1, follistatin (Fst) and adropin (Enho), and reduced activin E (Inhbe) expression. Gender had only a modest influence on hepatokine gene expression in the liver. Conclusion – The present results highlight the potential roles of hepatokines as a class of hormones that substantially influence nutritional regulation in both female and male mice. C 2019 Elsevier Masson S Nanyang Technological University S.S. is supported by a PhD grant from INSERM. P.G and A.M. are supported by grants from the Socie´te´ francophone du diabe`te and the Socie´te´ franc¸aise de nutrition. W.W. is supported by a start-up grant from the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. This work was also funded by ANR Hepatokind (to C.P. and H.G.). W.W., A.M., P.G. and H.G. were supported by grants from Re´gion Occitanie.

Published
2020
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9. A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response

Author

Anne-Françoise Burnol, Arnaud Polizzi, Marcio Do-Cruzeiro, Hervé Guillou, Emilie Tournier, Alison Iroz, Céline Lukowicz, Walter Wahli, Edwin Fouché, Solenne Marmier, Jean Girard, Renaud Dentin, Catherine Postic, Elodie Anthony, Fadila Benhamed, Françoise Levavasseur, Marion Régnier, Martine Daujat-Chavanieu, Yannick Lippi, Sandra Guilmeau, Véronique Fauveau, Sabine Gerbal-Chalouin, Michele Cauzac, Alexandra Montagner, 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), Université Fédérale Toulouse Midi-Pyrénées, 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), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Dentin, Renaud, Guillou, Hervé, Postic, Catherine, Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), 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-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Prévention et promotion de la cancérogénèse par les aliments (ToxAlim-PPCA), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Transcriptomic impact of Xenobiotics (E23 TRiX), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), H. Guillou's lab (TIM, ToxAlim) is supported by grants from Region Occitanie. W.W. was supported by a start-up grant from Lee Kong Chian School of Medicine, Nanyang Technological University. C. Postic's lab (U1016-Institut Cochin) is supported by grants from ChroME Network (Marie Curie Sklodowska Action H2020-MSCA-ITN-2015-675610), the Foundation for the Medical Research (FRM) (DEQ20150331744), and the European Foundation for the Study of Diabetes (EFSD) Novonordisk. H. Guillou's and C. Postic's labs are also supported by grants from the National Agency for Research (ANR) (ANR- 12BSV1-0025-ObeLiP and ANR -15-CE14-0026-Hepatokind). R. Dentin's lab (U1016-Institut Cochin) is supported by the European Research Council (ERC-2013-StG-336629) and the city of Paris (Projet Emergences-2011), Lee Kong Chian School of Medicine (LKCMedicine), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Plateforme Génome & Transcriptome (GET)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, FGF21, ChREBP, [SDV]Life Sciences [q-bio], sucrose preference, toxicologie alimentaire, 030209 endocrinology & metabolism, Context (language use), Biology, Carbohydrate metabolism, Response Elements, Toxicology, PPARα, Toxicology and food chain, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Animals, Cells, Cultured, Female, Fibroblast Growth Factors/genetics, Fibroblast Growth Factors/metabolism, Glucose/metabolism, Hepatocytes/metabolism, Mice, Inbred C57BL, Nuclear Proteins/genetics, Nuclear Proteins/metabolism, PPAR alpha/genetics, PPAR alpha/metabolism, Transcription Factors/genetics, Transcription Factors/metabolism, glucose intake, medicine, PPAR alpha, Receptor, Carbohydrate-responsive element-binding protein, Transcription factor, lcsh:QH301-705.5, Toxicologie, Toxicologie et chaîne alimentaire, ComputingMilieux_MISCELLANEOUS, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Nuclear Proteins, Fibroblast Growth Factors, Glucose, 030104 developmental biology, Endocrinology, Nuclear receptor, lcsh:Biology (General), Knockout mouse, Hepatocytes, Transcription Factors
Abstract

Summary While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp−/− mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp−/− mice. Unexpectedly, carbohydrate challenge of hepatic Pparα knockout mice also demonstrated a PPARα-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21., Graphical Abstract, Highlights • Fgf21 is a unique hepatic gene inducible by both catabolic and anabolic signals • The ChREBP-mediated induction of Fgf21 in hepatocytes requires PPARα • Loss of PPARα impairs Fgf21 promoter accessibility at the ChoRE • PPARα is required for the control of sucrose preference in vivo, FGF21 is a hepatokine with beneficial metabolic effects, including control of sucrose preference. Iroz et al. demonstrate that Fgf21 is a unique hepatic gene inducible by both fasting and glucose signals and that the transcription factors PPARα and ChREBP both regulate the endocrine control of sugar intake by hepatic FGF21.

Published
2017
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10. MondoA/ChREBP: The usual suspects of transcriptional glucose sensing; Implication in pathophysiology

Author

Sarah Ourabah, Sandra Guilmeau, Anne-Françoise Burnol, Jacques Montagne, Paul Richards, Catherine Postic, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Croissance et métabolisme chez la Drosophile (METABO), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, medicine.medical_specialty, ChREBP, Endocrinology, Diabetes and Metabolism, Glucose uptake, [SDV]Life Sciences [q-bio], Context (language use), Biology, Carbohydrate metabolism, 03 medical and health sciences, Glucose and lipid metabolism, Endocrinology, Internal medicine, medicine, Glucose homeostasis, Animals, Humans, cancer, Carbohydrate-responsive element-binding protein, Transcription factor, Mechanism (biology), Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Lipogenesis, Diabetes, 030104 developmental biology, Glucose, Energy Metabolism, Glycolysis, Transcription Factors, MondoA
Abstract

Identification of the Mondo glucose-responsive transcription factors family, including the MondoA and MondoB/ChREBP paralogs, has shed light on the mechanism whereby glucose affects gene transcription. They have clearly emerged, in recent years, as key mediators of glucose sensing by multiple cell types. MondoA and ChREBP have overlapping yet distinct expression profiles, which underlie their downstream targets and separate roles in regulating genes involved in glucose metabolism. MondoA can restrict glucose uptake and influences energy utilization in skeletal muscle, while ChREBP signals energy storage through de novo lipogenesis in liver and white adipose tissue. Because Mondo proteins mediate metabolic adaptations to changing glucose levels, a better understanding of cellular glucose sensing through Mondo proteins will likely uncover new therapeutic opportunities in the context of the imbalanced glucose homeostasis that accompanies metabolic diseases such as type 2 diabetes and cancer. Here, we provide an overview of structural homologies, transcriptional partners as well as the nutrient and hormonal mechanisms underlying Mondo proteins regulation. We next summarize their relative contribution to energy metabolism changes in physiological states and the evolutionary conservation of these pathways. Finally, we discuss their possible targeting in human pathologies.

Published
2017
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11. Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance

Author

François Canonne-Hergaux, Hervé Guillou, Carina Prip-Buus, Bruno Ragazzon, Lucie Popineau, Masaaki Komatsu, Lorenne Robert, Michèle Caüzac, Catherine Postic, Sandra Guilmeau, Pascale Bossard, Véronique Lenoir, Véronique Fauveau, Lucille Morzyglod, Nadège Carré, Anne-Françoise Burnol, ProdInra, Archive Ouverte, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-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)), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-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), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), ToxAlim (ToxAlim), 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)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), UMR 1416 Institut de recherche en santé digestive, Institut National de la Recherche Agronomique ( INRA ), IRSD U1220, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), and Institut National Polytechnique de Toulouse ( INPT ) -Institut National Polytechnique de Toulouse ( INPT )

Subjects
0301 basic medicine, medicine.medical_specialty, NF-E2-Related Factor 2, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Mice, 03 medical and health sciences, Growth factor receptor binding, Insulin resistance, Downregulation and upregulation, Internal medicine, medicine, Animals, désordre métabolique, Liver X receptor, Molecular Biology, Cyclin-Dependent Kinase Inhibitor p16, ComputingMilieux_MISCELLANEOUS, lipogenesis, Adaptor Proteins, Signal Transducing, Liver X Receptors, lipogénèse, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology, Insulin, fonction hépatique, Proteins, Articles, Cell Biology, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Receptor, Insulin, Insulin receptor, sensibilité à l'insuline, 030104 developmental biology, Endocrinology, Gene Expression Regulation, Liver, liver function, Gene Knockdown Techniques, Lipogenesis, biology.protein, Liver function, Insulin Resistance, Signal Transduction
Abstract

A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, while de novo lipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood. Here, we established a model of selective insulin resistance in mice by silencing an inhibitor of insulin receptor catalytic activity, the growth factor receptor binding protein 14 (Grb14) in liver. Indeed, Grb14 knockdown enhanced hepatic insulin signaling but also dramatically inhibited de novo fatty acid synthesis. In the liver of obese and insulin-resistant mice, downregulation of Grb14 markedly decreased blood glucose and improved liver steatosis. Mechanistic analyses showed that upon Grb14 knockdown, the release of p62/sqstm1, a partner of Grb14, activated the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn repressed the lipogenic nuclear liver X receptor (LXR). Our study reveals that Grb14 acts as a new signaling node that regulates lipogenesis and modulates insulin sensitivity in the liver by acting at a cross-road between the insulin receptor and the p62-Nrf2-LXR signaling pathways.

Published
2016
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12. RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3

Author

Anne-Françoise Burnol, Katia Cailliau, Edith Browaeys-Poly, Arlette Lescuyer, Christian Widmann, and Álvaro Cuesta-Marbán

Subjects
MAPK/ERK pathway, Cell signaling, Microinjections, Recombinant Fusion Proteins, Primary Cell Culture, Mechanistic Target of Rapamycin Complex 2, Biology, Biochemistry, Xenopus laevis, Cell Line, Tumor, Phosphoprotein Phosphatases, Animals, Humans, Enzyme Inhibitors, Phosphorylation, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, Mitogen-Activated Protein Kinase 1, PHLPP, Caspase 3, TOR Serine-Threonine Kinases, fungi, Ovary, Nuclear Proteins, p120 GTPase Activating Protein, Cell Biology, Peptide Fragments, Cell biology, Protein Structure, Tertiary, G2 Phase Cell Cycle Checkpoints, Gene Expression Regulation, Fibroblast growth factor receptor, Multiprotein Complexes, Proteolysis, Oocytes, Fibroblast Growth Factor 1, Female, Signal transduction, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Fibroblast growth factor receptors (FGFRs) are involved in proliferative and differentiation physiological responses. Deregulation of FGFR-mediated signaling involving the Ras/PI3K/Akt and the Ras/Raf/ERK MAPK pathways is causally involved in the development of several cancers. The caspase-3/p120 RasGAP module is a stress sensor switch. Under mild stress conditions, RasGAP is cleaved by caspase-3 at position 455. The resulting N-terminal fragment, called fragment N, stimulates anti-death signaling. When caspase-3 activity further increases, fragment N is cleaved at position 157. This generates a fragment, called N2, that no longer protects cells. Here, we investigated in Xenopus oocytes the impact of RasGAP and its fragments on FGF1-mediated signaling during G2/M cell cycle transition. RasGAP used its N-terminal Src homology 2 domain to bind FGFR once stimulated by FGF1, and this was necessary for the recruitment of Akt to the FGFR complex. Fragment N, which did not associate with the FGFR complex, favored FGF1-induced ERK stimulation, leading to accelerated G2/M transition. In contrast, fragment N2 bound the FGFR, and this inhibited mTORC2-dependent Akt Ser-473 phosphorylation and ERK2 phosphorylation but not phosphorylation of Akt on Thr-308. This also blocked cell cycle progression. Inhibition of Akt Ser-473 phosphorylation and entry into G2/M was relieved by PHLPP phosphatase inhibition. Hence, full-length RasGAP favors Akt activity by shielding it from deactivating phosphatases. This shielding was abrogated by fragment N2. These results highlight the role played by RasGAP in FGFR signaling and how graded stress intensities, by generating different RasGAP fragments, can positively or negatively impact this signaling.

Published
2015

13. T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism in mice

Author

Chiara Sartor, François Guillonneau, Philippe Veber, Laura Bachelot, Anne-Françoise Burnol, Angélique Gougelet, Cyril Torre, Albert Braeuning, Pierre-Damien Denechaud, Christine Perret, Céline Dubuquoy, Michael Schwarz, Cécile Godard, Tao Ye, Sabine Colnot, Marthe Moldes, Benoit Terris, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Département de Physiologie, Université de Montréal (UdeM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et de cytologie pathologiques [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme protéomique 3P5 [Institut Cochin] (3P5), 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 Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Medical University Graz, Bundesinstitut für Risikobewertung - Federal Institute for Risk Assessment (BfR), École pratique des hautes études (EPHE), GOUGELET, Angélique, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Male, [SDV]Life Sciences [q-bio], Biology, Transcriptome, Mice, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Gene expression, Animals, Humans, Gene Regulatory Networks, beta Catenin, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Hepatology, Liver Neoplasms, Lipid metabolism, Receptor Cross-Talk, HCCS, Lipid Metabolism, Molecular biology, Chromatin, 3. Good health, [SDV] Life Sciences [q-bio], Hepatocyte Nuclear Factor 4, Liver, Nuclear receptor, Hepatocyte nuclear factor 4, embryonic structures, Hepatocytes, 030211 gastroenterology & hepatology, Transcription Factor 7-Like 2 Protein
Abstract

β-catenin signaling can be both a physiological and oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20%-40% of hepatocellular carcinomas (HCCs) with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by T-cell factor (Tcf)−4 and β-catenin, transcriptome, and metabolome. We find that Tcf-4 DNA bindings depend on β-catenin. Tcf-4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf-4 on hepatocyte nuclear factor 4 (Hnf-4)-responsive elements. β-Catenin, Tcf-4, and Hnf-4α interact, dictating β-catenin transcription, which is antagonistic to that elicited by Hnf-4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. Conclusions: β-catenin patterns the zonal liver together with Tcf-4, Hnf-4α, and xenobiotic nuclear receptors. This network represses lipid metabolism and exacerbates glutamine, drug, and bile metabolism, mirroring HCCs with β-catenin mutational activation. (Hepatology 2014;59:2344–2357)

Published
2014
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14. Molecular Determinants of Grb14-Mediated Inhibition of Insulin Signaling

Author

Tarik Issad, Isabelle Broutin, Nadege Carre, Jean Girard, Cornelia Hampe, Dominique Perdereau, Lowenna J Holt, Katia Cailliau, Anne-Françoise Burnol, Diana Goenaga, Roger J. Daly, Edith Browaeys-Poly, 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), U693, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Sud (Paris 11), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Régulation des Signaux de Division, Université de Lille, Sciences et Technologies, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), 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 Lille-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Xenopus, Amino Acid Motifs, Plasma protein binding, Biology, Protein Serine-Threonine Kinases, 03 medical and health sciences, Insulin Antagonists, Mice, 0302 clinical medicine, Endocrinology, Protein-fragment complementation assay, Insulin receptor substrate, Chlorocebus aethiops, Animals, Humans, Insulin, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, 030304 developmental biology, Original Research, Adaptor Proteins, Signal Transducing, Mice, Knockout, 0303 health sciences, GRB7, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Biological activity, General Medicine, biology.organism_classification, Receptor, Insulin, Protein Structure, Tertiary, Insulin receptor, Biochemistry, 030220 oncology & carcinogenesis, COS Cells, biology.protein, Signal transduction, Protein Binding, Signal Transduction
Abstract

Grb14 belongs to the Grb7 family of molecular adapters and was identified as an inhibitor of insulin signaling. Grb14 binds to activated insulin receptors (IR) and inhibits their catalytic activity. To gain more insight into the Grb14 molecular mechanism of action, we generated various mutants and studied the Grb14-IR interaction using coimmunoprecipitation and bioluminescence resonance energy transfer (BRET) experiments. Biological activity was further analyzed using the Xenopus oocyte model and a functional complementation assay measuring cellular proliferation rate in Grb14 knockout mouse embryonic fibroblasts. These studies identified two important interaction sites, Grb14 L404-IR L1038 and Grb14 R385-IR K1168, involving the IR αC-helix and activation loop, respectively. Interestingly, the former involves residues that are likely to be crucial for the specificity of IR binding with regard to other members of the Grb7 family. In addition, mutation of the Grb14-S370 residue suggested that its phosphorylation status controlled the biological activity of the protein. We further demonstrated that insulin-induced Grb14-PDK1 interaction is required in addition to Grb14-IR binding to mediate maximal inhibition of insulin signaling. This study provides important insights into the molecular determinants of Grb14 action by demonstrating that Grb14 regulates insulin action at two levels, through IR binding and by interfering with downstream pathways. Indeed, a precise knowledge of the molecular mechanism of insulin signaling inhibition by Grb14 is a prerequisite for the development of insulin-sensitizing molecules to treat pathophysiological states such as obesity or type 2 diabetes.

Published
2009
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15. The PIR domain of Grb14 is an intrinsically unstructured protein: implication in insulin signaling

Author

Katia Cailliau, Anne-Françoise Burnol, Isabelle Broutin, Arnaud Ducruix, Dominique Perdereau, Karine Moncoq, Valéry Larue, Edith Browaeys-Poly, Laboratoire de biologie physico-chimique des protéines membranaires (LBPC-PM (UMR_7099)), Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), IFR 118 (UPRES EA 1033), Université de Lille, Sciences et Technologies, Laboratoire de Régulation des Signaux de Division, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Laboratoire d'enzymologie et biochimie structurales (LEBS), Centre National de la Recherche Scientifique (CNRS), Institut de biologie physico-chimique (IBPC (FR_550)), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and 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
Models, Molecular, Protein Conformation, Phosphorylated insulin receptor interacting region, Recombinant Fusion Proteins, Biophysics, Xenopus, Xenopus Proteins, SH2 domain, Biochemistry, src Homology Domains, 03 medical and health sciences, Unstructured protein, Xenopus laevis, Structural Biology, Genetics, Animals, Insulin, Kinase activity, Phosphorylation, Molecular Biology, Protein secondary structure, Nuclear Magnetic Resonance, Biomolecular, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Nitrogen Isotopes, 030302 biochemistry & molecular biology, GRB7, Signal transducing adaptor protein, Proteins, Cell Biology, biology.organism_classification, Receptor, Insulin, Protein Structure, Tertiary, Grb7 family, Insulin receptor, Meiosis, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], biology.protein, Oocytes, Signal transduction, Signal Transduction
Abstract

Grb14 belongs to the Grb7 family of adapter proteins and was identified as a negative regulator of insulin signal transduction. Its inhibitory effect on the insulin receptor kinase activity is controlled by a newly discovered domain called PIR. To investigate the biochemical and biophysical characteristics of this new domain, we cloned and purified recombinant PIR-SH2, PIR, and SH2 domains. The isolated PIR and PIR-SH2 domains were physiologically active and inhibited insulin-induced reinitiation of meiosis in the Xenopus oocytes system. However, NMR experiments on 15N-labelled PIR revealed that it did not present secondary structure. These results suggest that the PIR domain belongs to the growing family of intrinsically unstructured proteins.

Published
2003
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16. Basal promoter and enhancer element of yeast U6 snRNA gene

Author

Pierre Oudet, André Sentenac, Anne-Françoise Burnol, Patrick Schultz, Florence Margottin, Marie-Claude Marsolier, Unité de recherche Nutrition Azotée des Plantes (URNAP), Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration

Subjects
Transcription, Genetic, TATA box, Genes, Fungal, Molecular Sequence Data, Saccharomyces cerevisiae, Biology, 03 medical and health sciences, Transcription Factors, TFIII, Structural Biology, Transcription (biology), RNA, Small Nuclear, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA, Fungal, Promoter Regions, Genetic, Enhancer, Molecular Biology, Transcription factor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Base Sequence, BDP1, 030302 biochemistry & molecular biology, RNA, Fungal, Molecular biology, Chromatin, Enhancer Elements, Genetic, Mutation, Transcription preinitiation complex, Small nuclear RNA, Transcription Factors
Abstract

The yeast U6 snRNA gene, SNR6, transcribed by RNA polymerase III or C, is shown to have a mixed promoter with upstream, intragenic and downstream elements. The distant downstream B black behaves as a typical enhancer element. Required in vivo, and for transcription of chromatin templates in vitro, it was also active in reversed orientation. As shown by footprinting and electron microscopy, the factor TFIIIC, or τ, bound the B block in an oriented manner and was able to induce DNA looping. The factor TFIIIC appeared to act via a weak A block located at position + 21. This A block-related motif was essential in vivo and with chromatin templates. When changed into a consensus A block it favored DNA leaping by TFIIIC firmly anchored on the B block, and activated a B block lacking gene in vivo and in vitro. The role of the TATA box at -30 was most apparent using a purified transcription system. With the A block, it appeared to contribute to start site selection. The results suggest a model where three weak promoter elements collaborate to assemble the transcription complex by DNA leaping and synergistic protein-DNA interactions.

Published
1993

17. Insulin resistance of glucose metabolism in isolated brown adipocytes of lactating rats. Evidence for a post-receptor defect in insulin action

Author

S Ebner, Anne-Françoise Burnol, Jean-Philippe Girard, and J. Kande

Subjects
medicine.medical_specialty, medicine.medical_treatment, Adipose tissue, Pyruvate Dehydrogenase Complex, Carbohydrate metabolism, Biology, Biochemistry, Insulin resistance, Adipose Tissue, Brown, Pregnancy, Internal medicine, Brown adipose tissue, medicine, Animals, Insulin, Lactation, Phosphorylation, Molecular Biology, Cells, Cultured, Rats, Inbred Strains, Cell Biology, Protein-Tyrosine Kinases, medicine.disease, Pyruvate dehydrogenase complex, Receptor, Insulin, Animals, Suckling, Rats, Insulin receptor, Kinetics, Endocrinology, medicine.anatomical_structure, Glucose, Lipogenesis, biology.protein, Glucose Clamp Technique, Female, Insulin Resistance, Research Article
Abstract

The mechanism responsible for the insulin resistance described in vivo in brown adipose tissue (BAT) of lactating rats was investigated. The effect of insulin on glucose metabolism was studied on isolated brown adipocytes of non-lactating and lactating rats. Insulin stimulation of total glucose metabolism is 50% less in brown adipocytes from lactating than from non-lactating rats. This reflects a decreased effect of insulin on glucose oxidation and lipogenesis. However, the effect of noradrenaline (8 microM) on glucose metabolism was preserved in brown adipocytes from lactating rats as compared with non-lactating rats. The number of insulin receptors is similar in BAT of lactating and non-lactating rats. The insulin-receptor tyrosine kinase activity is not altered during lactation, for receptor autophosphorylation as well as tyrosine kinase activity towards the synthetic peptide poly(Glu4-Tyr1). The defect in the action of insulin is thus localized at a post-receptor level. The insulin stimulation of pyruvate dehydrogenase activity during euglycaemic/hyperinsulinaemic clamps is 2-fold lower in BAT from lactating than from non-lactating rats. However, the percentage of active form of pyruvate dehydrogenase is similar in non-lactating and lactating rats (8.6% versus 8.9% in the basal state, and 37.0% versus 32.3% during the clamp). A decrease in the amount of pyruvate dehydrogenase is likely to be involved in the insulin resistance described in BAT during lactation.

Published
1990

18. Regulation by insulin of glucose metabolism in mammary gland of anaesthetized lactating rats. Stimulation of phosphofructokinase-1 by fructose 2,6-bisphosphate and activation of acetyl-CoA carboxylase

Author

Pascal Ferré, S Ebner, Jean-Philippe Girard, and Anne-Françoise Burnol

Subjects
Blood Glucose, medicine.medical_specialty, medicine.medical_treatment, Phosphofructokinase-1, Carbohydrate metabolism, Biology, Biochemistry, chemistry.chemical_compound, Mammary Glands, Animal, Pregnancy, Internal medicine, medicine, Fructosediphosphates, Animals, Insulin, Lactation, Phosphofructokinase 1, Molecular Biology, Acetyl-CoA carboxylase, Fructose, Rats, Inbred Strains, Cell Biology, Pyruvate carboxylase, Rats, Enzyme Activation, Isoenzymes, Endocrinology, Glucose, chemistry, Fructose 2,6-bisphosphate, Enzyme Induction, Fructolysis, Female, Research Article, Acetyl-CoA Carboxylase
Abstract

The effect of insulin on glucose metabolism in mammary gland was studied by the euglycaemic/hyperinsulinaemic-clamp technique. Measurement of metabolite concentrations and enzyme activities in the mammary gland suggests two sites of action of insulin: phosphofructokinase-1 and acetyl-coA carboxylase. The increase in phosphofructokinase-1 activity could be linked to the 2-fold increase in fructose 2,6-bisphosphate concentration, since no change in maximal activity and in sensitivity of the enzyme toward fructose 6-phosphate was detected in vitro.

Published
1988

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