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1. 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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2. AMPKα1 controls hepatocyte proliferation independently of energy balance by regulating Cyclin A2 expression

Author

Véronique Fauveau, Géraldine Gentric, Jacques-Emmanuel Guidotti, J. Leclerc, Benoit Viollet, Grégory Merlen, Séverine Celton-Morizur, Marc Foretz, and Chantal Desdouets

Subjects
Hepatology, AMPK, G1/S transition, AMP-Activated Protein Kinases, Biology, Liver regeneration, Liver Regeneration, S Phase, Mice, Inbred C57BL, Mice, AMP-activated protein kinase, Hepatocytes, medicine, biology.protein, Cancer research, Animals, Hepatocyte growth factor, Energy Metabolism, Protein kinase A, Cyclin A2, PI3K/AKT/mTOR pathway, Cell Proliferation, medicine.drug
Abstract

Background AMP-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status that contributes to restoration of energy homeostasis by slowing down ATP-consuming pathways and activating ATP-producing pathways. Unexpectedly, in different systems, AMPK is also required for proper cell division. In the current study, we evaluated the potential effect of the AMPK catalytic subunit, AMPKα1, on hepatocyte proliferation. Methods Hepatocyte proliferation was determined in AMPKα1 knockout and wild-type mice in vivo after two thirds partial hepatectomy, and in vitro in primary hepatocyte cultures. The activities of metabolic and cell cycle-related signaling pathways were measured. Results After partial hepatectomy, hepatocytes proliferated rapidly, correlating with increased AMPK phosphorylation. Deletion of AMPKα1 delayed liver regeneration by impacting on G1/S transition phase. The proliferative defect of AMPKα1-deficient hepatocytes was cell autonomous, and independent of energy balance. The priming phase, lipid droplet accumulation, protein anabolic responses and growth factor activation after partial hepatectomy occurred normally in the absence of AMPKα1 activity. By contrast, mRNA and protein expression of cyclin A2, a key driver of S phase progression, were compromised in the absence of AMPK activity. Importantly, AMPKα1 controlled cyclin A2 transcription mainly through the ATF/CREB element. Conclusions Our study highlights a novel role for AMPKα1 as a positive regulator of hepatocyte division occurring independently of energy balance.

Published
2014
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3. Growth factor receptor binding protein 14 inhibition triggers insulin-induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma

Author

Bruno Ragazzon, Anne-Françoise Burnol, Lucie Popineau, Olivier Scatton, Sandra Guilmeau, Michèle Caüzac, Véronique Fauveau, Pierre-Damien Denechaud, Chantal Desdouets, Laetitia Fartoux, Lucille Morzyglod, Julien Planchais, Mireille Vasseur-Cognet, Catherine Postic, Lluis Fajas, Christèle Desbois-Mouthon, Olivier Rosmorduc, 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), Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Département de Physiologie, Université de Montréal [Montréal], Centre Intégratif de Génomique, Université de Lausanne, Institut d'écologie et des sciences de l'environnement de Paris (IEES), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA), Institut d'écologie et des sciences de l'environnement de Paris (IEES (UMR_7618 / UMR_D_242 / UMR_A_1392 / UM_113) ), Institut National de la Recherche Agronomique (INRA)-Sorbonne Université (SU)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Recherche Saint-Antoine (CRSA), Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Service de Chirurgie Hépatobiliaire et Transplantation, Hôpital Universitaire Pitié Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP - HP), Agence nationale de la recherche [ANR-06-Grb14, ANR-10-Wnt-Metaboliv, ANR-09-JCJC-0057], Fondation pour la Recherche Medicale (Labelisation Equipe), Institut National du Cancer [INCa-DGOS_5790], Ligue contre le Cancer (Comite de Paris), French Ministry of Research, Fondation pour la Recherche Medicale, 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 Montréal (UdeM), Université de Lausanne = University of Lausanne (UNIL), Institut d'écologie et des sciences de l'environnement de Paris (iEES), Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Institut d'écologie et des sciences de l'environnement de Paris (iEES Paris), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU), 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 ), Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Université de Montréal, Institut d'écologie et des sciences de l'environnement de Paris ( IEES ), Institut National de la Recherche Agronomique ( INRA ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), IEES Institut d'Ecologie et des Sciences de l'Environnement de Paris, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Hépato-Gastroentérologie, CHU Caen, Hôpital Universitaire Pitié Salpêtrière, Assistance Publique - Hôpitaux de Paris ( AP - HP ), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and ProdInra, Archive Ouverte

Subjects
0301 basic medicine, Male, liver cell carcinoma, insulin, Carcinoma, Hepatocellular, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Down-Regulation, souris, Sensitivity and Specificity, 03 medical and health sciences, Growth factor receptor binding, Mice, Random Allocation, Downregulation and upregulation, Growth factor receptor, Cell Line, Tumor, medicine, E2F1, hépatocarcinome, Animals, Humans, Mechanistic target of rapamycin, insuline, Cells, Cultured, Adaptor Proteins, Signal Transducing, Cell Proliferation, [ SDV ] Life Sciences [q-bio], Hepatology, biology, Chemistry, Insulin, Liver Neoplasms, Receptor, Insulin, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Insulin receptor, Disease Models, Animal, 030104 developmental biology, Diabetes Mellitus, Type 2, Hepatocyte nuclear factor 4 alpha, biology.protein, Cancer research, Hepatocytes
Abstract

Metabolic diseases such as obesity and type 2 diabetes are recognized as independent risk factors for hepatocellular carcinoma (HCC). Hyperinsulinemia, a hallmark of these pathologies, is suspected to be involved in HCC development. The molecular adapter growth factor receptor binding protein 14 (Grb14) is an inhibitor of insulin receptor catalytic activity, highly expressed in the liver. To study its involvement in hepatocyte proliferation, we specifically inhibited its liver expression using a short hairpin RNA strategy in mice. Enhanced insulin signaling upon Grb14 inhibition was accompanied by a transient induction of S-phase entrance by quiescent hepatocytes, indicating that Grb14 is a potent repressor of cell division. The proliferation of Grb14-deficient hepatocytes was cell-autonomous as it was also observed in primary cell cultures. Combined Grb14 down-regulation and insulin signaling blockade using pharmacological approaches as well as genetic mouse models demonstrated that Grb14 inhibition–mediated hepatocyte division involved insulin receptor activation and was mediated by the mechanistic target of rapamycin complex 1–S6K pathway and the transcription factor E2F1. In order to determine a potential dysregulation in GRB14 gene expression in human pathophysiology, a collection of 85 human HCCs was investigated. This revealed a highly significant and frequent decrease in GRB14 expression in hepatic tumors when compared to adjacent nontumoral parenchyma, with 60% of the tumors exhibiting a reduced Grb14 mRNA level. Conclusion: Our study establishes Grb14 as a physiological repressor of insulin mitogenic action in the liver and further supports that dysregulation of insulin signaling is associated with HCC. (Hepatology 2017;65:1352-1368).

Published
2016
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4. Diet and Gastrointestinal Bypass–Induced Weight Loss

Author

Megan E. Drew, Rachel L. Batterham, Cigdem Gelegen, Efthimia Karra, Agharul I. Choudhury, Fabrizio Andreelli, Dominic J. Withers, Véronique Fauveau, Benoit Viollet, and Keval Chandarana

Subjects
Leptin, Male, endocrine system, medicine.medical_specialty, Diet, Reducing, Colon, Endocrinology, Diabetes and Metabolism, Gastric Bypass, Radioimmunoassay, Enzyme-Linked Immunosorbent Assay, Biology, Glucagon, Energy homeostasis, Mice, Random Allocation, Glucagon-Like Peptide 1, Weight loss, Internal medicine, Weight Loss, Internal Medicine, medicine, Animals, Peptide YY, Obesity, Diet, Fat-Restricted, Analysis of Variance, Reverse Transcriptase Polymerase Chain Reaction, digestive, oral, and skin physiology, Glucagon-like peptide-1, Ghrelin, Endocrinology, Postprandial, Gastric Mucosa, medicine.symptom, Obesity Studies, hormones, hormone substitutes, and hormone antagonists
Abstract

OBJECTIVE Bariatric surgery causes durable weight loss. Gut hormones are implicated in obesity pathogenesis, dietary failure, and mediating gastrointestinal bypass (GIBP) surgery weight loss. In mice, we determined the effects of diet-induced obesity (DIO), subsequent dieting, and GIBP surgery on ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). To evaluate PYY’s role in mediating weight loss post-GIBP, we undertook GIBP surgery in PyyKO mice. RESEARCH DESIGN AND METHODS Male C57BL/6 mice randomized to a high-fat diet or control diet were killed at 4-week intervals. DIO mice underwent switch to ad libitum low-fat diet (DIO-switch) or caloric restriction (CR) for 4 weeks before being killed. PyyKO mice and their DIO wild-type (WT) littermates underwent GIBP or sham surgery and were culled 10 days postoperatively. Fasting acyl-ghrelin, total PYY, active GLP-1 concentrations, stomach ghrelin expression, and colonic Pyy and glucagon expression were determined. Fasting and postprandial PYY and GLP-1 concentrations were assessed 30 days postsurgery in GIBP and sham pair-fed (sham.PF) groups. RESULTS DIO progressively reduced circulating fasting acyl-ghrelin, PYY, and GLP-1 levels. CR and DIO-switch caused weight loss but failed to restore circulating PYY to weight-appropriate levels. After GIBP, WT mice lost weight and exhibited increased circulating fasting PYY and colonic Pyy and glucagon expression. In contrast, the acute effects of GIBP on body weight were lost in PyyKO mice. Fasting PYY and postprandial PYY and GLP-1 levels were increased in GIBP mice compared with sham.PF mice. CONCLUSIONS PYY plays a key role in mediating the early weight loss observed post-GIBP, whereas relative PYY deficiency during dieting may compromise weight-loss attempts.

Published
2011
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5. The Transcription Factor COUP-TFII Is Negatively Regulated by Insulin and Glucose via Foxo1- and ChREBP-Controlled Pathways

Author

Ilham Kharroubi, Anaïs Perilhou, Mireille Vasseur-Cognet, Carole Hénique, Véronique Fauveau, Christophe Magnan, Catherine Postic, Cécile Tourrel-Cuzin, Carina Prip-Buus, Tadahiro Kitamura, Laboratoire de physiopathologie de la nutrition (LPN), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Probabilités et Modèles Aléatoires (LPMA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Earth and Planetary Sciences [Kobe], Kobe University, 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 Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
Male, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Mice, Obese, FOXO1, COUP Transcription Factor II, Mice, 0302 clinical medicine, Insulin-Secreting Cells, Insulin receptor substrate, Glucokinase, Insulin Secretion, Insulin, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, 0303 health sciences, biology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Forkhead Box Protein O1, Nuclear Proteins, Forkhead Transcription Factors, Articles, 3. Good health, Insulin oscillation, Liver, 030220 oncology & carcinogenesis, Beta cell, Signal Transduction, medicine.medical_specialty, Down-Regulation, Cell Line, 03 medical and health sciences, Downregulation and upregulation, Internal medicine, medicine, Animals, RNA, Messenger, Molecular Biology, Triglycerides, 030304 developmental biology, Cell Biology, Rats, Mice, Inbred C57BL, Insulin receptor, Glucose, Endocrinology, Hepatocytes, biology.protein, Transcription Factors
Abstract

COUP-TFII has an important role in regulating metabolism in vivo. We showed this previously by deleting COUP-TFII from pancreatic beta cells in heterozygous mutant mice, which led to abnormal insulin secretion. Here, we report that COUP-TFII expression is reduced in the pancreas and liver of mice refed with a carbohydrate-rich diet and in the pancreas and liver of hyperinsulinemic and hyperglycemic mice. In pancreatic beta cells, COUP-TFII gene expression is repressed by secreted insulin in response to glucose through Foxo1 signaling. Ex vivo COUP-TFII reduces insulin production and secretion. Our results suggest that beta cell insulin secretion is under the control of an autocrine positive feedback loop by alleviating COUP-TFII repression. In hepatocytes, both insulin, through Foxo1, and high glucose concentrations repress COUP-TFII expression. We demonstrate that this negative glucose effect involves ChREBP expression. We propose that COUP-TFII acts in a coordinate fashion to control insulin secretion and glucose metabolism.

Published
2008
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6. Intestinal Gluconeogenesis Is a Key Factor for Early Metabolic Changes after Gastric Bypass but Not after Gastric Lap-Band in Mice

Author

Carine Zitoun, Jocelyne Leclerc, Gilles Mithieux, Bruno Pillot, Benoit Viollet, Fabrizio Andreelli, Véronique Fauveau, Christophe Magnan, A. Duchampt, Xavier Fioramonti, Lara Ribeiro, Roberte Aubert, Stéphanie Troy, Laure Laval, Stéphanie Migrenne, Marc Foretz, Maud Soty, Bernard Thorens, Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et cerveau (U1213, U855), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de physiopathologie de la nutrition (LPN), Université Paris Diderot - Paris 7 (UPD7)-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), Institut Fédératif de Recherche Alfred Jost (IFRAJ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nutrition, diabète et cerveau (NUDICE), Université de Lausanne = University of Lausanne (UNIL), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Di Carlo, Marie-Ange

Subjects
Male, medicine.medical_specialty, Time Factors, Gastroplasty, Physiology, medicine.medical_treatment, Gastric Bypass, HUMDISEASE, Biology, Carbohydrate metabolism, medicine.disease_cause, Models, Biological, Eating, Mice, Insulin resistance, Internal medicine, Intestine, Small, medicine, Animals, Insulin, Glucose homeostasis, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, Glucose Transporter Type 2, Mice, Knockout, Glucose Transporter Type 1, Portal Vein, Gastric bypass surgery, digestive, oral, and skin physiology, Gluconeogenesis, Reproducibility of Results, Type 2 Diabetes Mellitus, Cell Biology, medicine.disease, Dietary Fats, Obesity, Morbid, Mice, Inbred C57BL, Glucose, Endocrinology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Insulin Resistance
Abstract

International audience; Unlike the adjustable gastric banding procedure (AGB), Roux-en-Y gastric bypass surgery (RYGBP) in humans has an intriguing effect: a rapid and substantial control of type 2 diabetes mellitus (T2DM). We performed gastric lap-band (GLB) and entero-gastro anastomosis (EGA) procedures in C57Bl6 mice that were fed a high-fat diet. The EGA procedure specifically reduced food intake and increased insulin sensitivity as measured by endogenous glucose production. Intestinal gluconeogenesis increased after the EGA procedure, but not after gastric banding. All EGA effects were abolished in GLUT-2 knockout mice and in mice with portal vein denervation. We thus provide mechanistic evidence that the beneficial effects of the EGA procedure on food intake and glucose homeostasis involve intestinal gluconeogenesis and its detection via a GLUT-2 and hepatoportal sensor pathway.

Published
2008
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7. The MODY1 Gene for Hepatocyte Nuclear Factor 4α and a Feedback Loop Control COUP-TFII Expression in Pancreatic Beta Cells

Author

Véronique Fauveau, Mireille Vasseur-Cognet, Donald K. Scott, Claes B. Wollheim, Ilham Kharroubi, Haiyan Wang, Anaïs Perilhou, Pili Zhang, and Cécile Tourrel-Cuzin

Subjects
Male, Transcriptional Activation, endocrine system, Biology, digestive system, Hepatocyte Nuclear Factor 4/genetics/metabolism, Cell Line, COUP Transcription Factor II, Mice, Transactivation, Insulin-Secreting Cells/metabolism, Insulin-Secreting Cells, medicine, Animals, Gene Regulatory Networks, COUP Transcription Factor II/genetics/metabolism, ddc:612, Promoter Regions, Genetic, Molecular Biology, Transcription factor, COUP-TFII, Pancreatic islets, Promoter, Articles, Cell Biology, Molecular biology, Rats, Mice, Inbred C57BL, medicine.anatomical_structure, Hepatocyte Nuclear Factor 4, Hepatocyte nuclear factor 4, Mutation, PAX4, Beta cell
Abstract

Pancreatic islet beta cell differentiation and function are dependent upon a group of transcription factors that maintain the expression of key genes and suppress others. Knockout mice with the heterozygous deletion of the gene for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) or the complete disruption of the gene for hepatocyte nuclear factor 4alpha (HNF4alpha) in pancreatic beta cells have similar insulin secretion defects, leading us to hypothesize that there is transcriptional cross talk between these two nuclear receptors. Here, we demonstrate specific HNF4alpha activation of a reporter plasmid containing the COUP-TFII gene promoter region in transfected pancreatic beta cells. The stable association of the endogenous HNF4alpha with a region of the COUP-TFII gene promoter that contains a direct repeat 1 (DR-1) binding site was revealed by chromatin immunoprecipitation. Mutation experiments showed that this DR-1 site is essential for HNF4alpha transactivation of COUP-TFII. The dominant negative suppression of HNF4alpha function decreased endogenous COUP-TFII expression, and the specific inactivation of COUP-TFII by small interfering RNA caused HNF4alpha mRNA levels in 832/13 INS-1 cells to decrease. This positive regulation of HNF4alpha by COUP-TFII was confirmed by the adenovirus-mediated overexpression of human COUP-TFII (hCOUP-TFII), which increased HNF4alpha mRNA levels in 832/13 INS-1 cells and in mouse pancreatic islets. Finally, hCOUP-TFII overexpression showed that there is direct COUP-TFII autorepression, as COUP-TFII occupies the proximal DR-1 binding site of its own gene in vivo. Therefore, COUP-TFII may contribute to the control of insulin secretion through the complex HNF4alpha/maturity-onset diabetes of the young 1 (MODY1) transcription factor network operating in beta cells.

Published
2008
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8. 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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9. Hepatic Glucokinase Is Required for the Synergistic Action of ChREBP and SREBP-1c on Glycolytic and Lipogenic Gene Expression

Author

Jean Girard, Renaud Dentin, Mark A. Magnuson, Fadila Benhamed, Pascal Ferré, Catherine Postic, Fabienne Foufelle, Véronique Fauveau, and Jean-Paul Pégorier

Subjects
Time Factors, Transcription, Genetic, Biochemistry, Mice, chemistry.chemical_compound, Glucokinase, Glycolysis, RNA, Small Interfering, Cells, Cultured, Mice, Knockout, Regulation of gene expression, biology, Glycogen, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Reverse Transcriptase Polymerase Chain Reaction, Nuclear Proteins, DNA-Binding Proteins, Fatty acid synthase, Liver, Carbohydrate Metabolism, Sterol Regulatory Element Binding Protein 1, Signal Transduction, medicine.medical_specialty, Immunoblotting, Pyruvate Kinase, Glucose-6-Phosphate, Mice, Transgenic, Carbohydrate metabolism, Adenoviridae, Internal medicine, medicine, Animals, RNA, Messenger, Molecular Biology, Cell Nucleus, Pentosephosphates, Acetyl-CoA carboxylase, Proteins, Cell Biology, Blotting, Northern, Lipid Metabolism, Mice, Inbred C57BL, Kinetics, Glucose, Endocrinology, Gene Expression Regulation, Microscopy, Fluorescence, Glucose 6-phosphate, chemistry, CCAAT-Enhancer-Binding Proteins, Hepatocytes, biology.protein, RNA, Fatty Acid Synthases, Acetyl-CoA Carboxylase, Transcription Factors
Abstract

Hepatic glucokinase (GK) catalyzes the phosphorylation of glucose to glucose 6-phosphate (G6P), a step which is essential for glucose metabolism in liver as well as for the induction of glycolytic and lipogenic genes. The sterol regulatory element-binding protein-1c (SREBP-1c) has emerged as a major mediator of insulin action on hepatic gene expression, but the extent to which its transcriptional effect is caused by an increased glucose metabolism remains unclear. Through the use of hepatic GK knockout mice (hGK-KO) we have shown that the acute stimulation by glucose of l-pyruvate kinase (l-PK), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and Spot 14 genes requires GK expression. To determine whether the effect of SREBP-1c requires GK expression and subsequent glucose metabolism, a transcriptionally active form of SREBP-1c was overexpressed both in vivo and in primary cultures of control and hGK-KO hepatocytes. Our results demonstrate that the synergistic action of SREBP-1c and glucose metabolism via GK is necessary for the maximal induction of l-PK, ACC, FAS, and Spot 14 gene expression. Indeed, in hGK-KO hepatocytes overexpressing SREBP-1c, the effect of glucose on glycolytic and lipogenic genes is lost because of the impaired ability of these hepatocytes to efficiently metabolize glucose, despite a marked increase in low K(m) hexokinase activity. Our studies also reveal that the loss of glucose effect observed in hGK-KO hepatocytes is associated with a decreased in the carbohydrate responsive element-binding protein (ChREBP) gene expression, a transcription factor suggested to mediate glucose signaling in liver. Decreased ChREBP gene expression, achieved using small interfering RNA, results in a loss of glucose effect on endogenous glycolytic (l-PK) and lipogenic (FAS, ACC) gene expression, thereby demonstrating the direct implication of ChREBP in glucose action. Together these results support a model whereby both SREBP-1c and glucose metabolism, acting via ChREBP, are necessary for the dietary induction of glycolytic and lipogenic gene expression in liver.

Published
2004
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10. Enhancing liver mitochondrial fatty acid oxidation capacity in obese mice improves insulin sensitivity independently of hepatic steatosis

Author

Catherine Esnous, Marie Akkaoui, Jean Girard, Julia Monsénégo, Valentin Tavernier, Abdelhak Mansouri, Véronique Fauveau, Véronique Lenoir, Carina Prip-Buus, 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), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Mice, Obese, Mitochondria, Liver, Adenoviridae, Glucaric Acid, Mice, 03 medical and health sciences, 0302 clinical medicine, Carnitine palmitoyltransferase 1, Insulin resistance, Internal medicine, Glucose Intolerance, medicine, Animals, Obesity, ComputingMilieux_MISCELLANEOUS, Adiposity, 030304 developmental biology, 0303 health sciences, Carnitine O-Palmitoyltransferase, Hepatology, biology, Body Weight, Fatty Acids, Fatty liver, Lipid Metabolism, medicine.disease, 3. Good health, Fatty Liver, Malonyl Coenzyme A, Mice, Inbred C57BL, Insulin receptor, Endocrinology, Lipotoxicity, 030220 oncology & carcinogenesis, Lipogenesis, biology.protein, Insulin Resistance, Steatosis, Metabolic syndrome, Oxidation-Reduction
Abstract

Background & Aims Despite major public health concern, therapy for non-alcoholic fatty liver, the liver manifestation of the metabolic syndrome often associated with insulin resistance (IR), remains elusive. Strategies aiming to decrease liver lipogenesis effectively corrected hepatic steatosis and IR in obese animals. However, they also indirectly increased mitochondrial long-chain fatty acid oxidation (mFAO) by decreasing malonyl-CoA, a lipogenic intermediate, which is the allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1A), the key enzyme of mFAO. We thus addressed whether enhancing hepatic mFAO capacity, through a direct modulation of liver CPT1A/malonyl-CoA partnership, can reverse an already established hepatic steatosis and IR in obese mice. Methods Adenovirus-mediated liver expression of a malonyl-CoA-insensitive CPT1A (CPT1mt) in high-fat/high-sucrose (HF/HS) diet-induced or genetically ( ob / ob ) obese mice was followed by metabolic and physiological investigations. Results In association with increased hepatic mFAO capacity, liver CPT1mt expression improved glucose tolerance and insulin response to a glucose load in HF/HS and ob / ob mice, showing increased insulin sensitivity, and corrected IR in ob / ob mice. Surprisingly, hepatic steatosis was not affected in CPT1mt-expressing obese mice, indicating a clear dissociation between hepatic steatosis and IR. Moreover, liver CPT1mt expression rescued HF/HS-induced impaired hepatic insulin signaling at the level of IRS-1, IRS-2, Akt, and GSK-3β, most likely through the observed decrease in the HF/HS-induced accumulation of lipotoxic lipids, oxidative stress, and JNK activation. Conclusions Enhancing hepatic mFAO capacity is sufficient to reverse a state of IR and glucose intolerance in obese mice independently of hepatic steatosis.

Published
2012
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12. Liver-Specific Inhibition of ChREBP Improves Hepatic Steatosis and Insulin Resistance in ob/ob Mice

Author

Fabienne Foufelle, Jason R.B. Dyck, Catherine Postic, Jean Girard, Fadila Benhamed, Isabelle Hainault, Véronique Fauveau, Renaud Dentin, [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Blood Glucose, Leptin, Male, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Mice, Obese, White adipose tissue, Fatty Acids, Nonesterified, Mice, 0302 clinical medicine, Insulin, RNA, Small Interfering, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Fatty liver, Nuclear Proteins, Lipids, 3. Good health, Adipose Tissue, Liver, 030220 oncology & carcinogenesis, Lipogenesis, Glycogen, Signal Transduction, medicine.medical_specialty, Down-Regulation, Transfection, 03 medical and health sciences, Insulin resistance, Internal medicine, Dietary Carbohydrates, Internal Medicine, medicine, Animals, Obesity, RNA, Messenger, Muscle, Skeletal, Carbohydrate-responsive element-binding protein, Triglycerides, 030304 developmental biology, Glucose Tolerance Test, medicine.disease, Fatty Liver, Insulin receptor, Glucose, Endocrinology, biology.protein, Insulin Resistance, Steatosis, Transcription Factors
Abstract

Obesity is a metabolic disorder often associated with type 2 diabetes, insulin resistance, and hepatic steatosis. Leptin-deficient (ob/ob) mice are a well-characterized mouse model of obesity in which increased hepatic lipogenesis is thought to be responsible for the phenotype of insulin resistance. We have recently demonstrated that carbohydrate responsive element–binding protein (ChREBP) plays a key role in the control of lipogenesis through the transcriptional regulation of lipogenic genes, including acetyl-CoA carboxylase and fatty acid synthase. The present study reveals that ChREBP gene expression and ChREBP nuclear protein content are significantly increased in liver of ob/ob mice. To explore the involvement of ChREBP in the physiopathology of hepatic steatosis and insulin resistance, we have developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) were used to inhibit ChREBP expression in vivo. Liver-specific inhibition of ChREBP in ob/ob mice markedly improved hepatic steatosis by specifically decreasing lipogenic rates. Correction of hepatic steatosis also led to decreased levels of plasma triglycerides and nonesterified fatty acids. As a consequence, insulin signaling was improved in liver, skeletal muscles, and white adipose tissue, and overall glucose tolerance and insulin sensitivity were restored in ob/ob mice after a 7-day treatment with the recombinant adenovirus expressing shRNA against ChREBP. Taken together, our results demonstrate that ChREBP is central for the regulation of lipogenesis in vivo and plays a determinant role in the development of the hepatic steatosis and of insulin resistance in ob/ob mice.

Published
2006
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