8 results on '"Emilie Dorchies"'
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2. Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis
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Hélène Dehondt, Arianna Marino, Laura Butruille, Denis A. Mogilenko, Arielle C. Nzoussi Loubota, Oscar Chávez-Talavera, Emilie Dorchies, Emmanuelle Vallez, Joel Haas, Bruno Derudas, Antonino Bongiovanni, Meryem Tardivel, Folkert Kuipers, Philippe Lefebvre, Sophie Lestavel, Anne Tailleux, David Dombrowicz, Sandrine Caron, and Bart Staels
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White adipose tissue ,Nuclear receptor FXR ,Inflammation ,Oxidative stress ,Glucose metabolism ,Internal medicine ,RC31-1245 - Abstract
Objective: Obesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. The bile acid (BA)-activated nuclear Farnesoid X Receptor (FXR) controls systemic glucose and lipid metabolism. Here, we studied the role of FXR in adipose tissue function. Methods: We first investigated the immune phenotype of epididymal WAT (eWAT) from high fat diet (HFD)-fed whole-body FXR-deficient (FXR−/−) mice by flow cytometry and gene expression analysis. We then generated adipocyte-specific FXR-deficient (Ad-FXR−/−) mice and analyzed systemic and eWAT metabolism and immune phenotype upon HFD feeding. Transcriptomic analysis was done on mature eWAT adipocytes from HFD-fed Ad-FXR−/− mice. Results: eWAT from HFD-fed whole-body FXR−/− and Ad-FXR−/− mice displayed decreased pro-inflammatory macrophage infiltration and inflammation. Ad-FXR−/− mice showed lower blood glucose concentrations, improved systemic glucose tolerance and WAT insulin sensitivity and oxidative stress. Transcriptomic analysis identified Gsta4, a modulator of oxidative stress in WAT, as the most upregulated gene in Ad-FXR−/− mouse adipocytes. Finally, chromatin immunoprecipitation analysis showed that FXR binds the Gsta4 gene promoter. Conclusions: These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.
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- 2023
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3. Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver
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Vanessa Dubois, Céline Gheeraert, Wouter Vankrunkelsven, Julie Dubois‐Chevalier, Hélène Dehondt, Marie Bobowski‐Gerard, Manjula Vinod, Francesco Paolo Zummo, Fabian Güiza, Maheul Ploton, Emilie Dorchies, Laurent Pineau, Alexis Boulinguiez, Emmanuelle Vallez, Eloise Woitrain, Eric Baugé, Fanny Lalloyer, Christian Duhem, Nabil Rabhi, Ronald E van Kesteren, Cheng‐Ming Chiang, Steve Lancel, Hélène Duez, Jean‐Sébastien Annicotte, Réjane Paumelle, Ilse Vanhorebeek, Greet Van den Berghe, Bart Staels, Philippe Lefebvre, and Jérôme Eeckhoute
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liver injury ,NFIL3 ,PAR‐bZIP ,sepsis ,super‐enhancer ,Biology (General) ,QH301-705.5 ,Medicine (General) ,R5-920 - Abstract
Abstract Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver‐identity (LIVER‐ID) transcription factor (TF) network, initiated by rapid LIVER‐ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER‐ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co‐recruitment of LIVER‐ID TFs and decommissioning of BRD4 super‐enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER‐ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients.
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- 2020
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4. Farnesoid X Receptor Activation in Brain Alters Brown Adipose Tissue Function via the Sympathetic System
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Benjamin Deckmyn, Dorothée Domenger, Chloé Blondel, Sarah Ducastel, Emilie Nicolas, Emilie Dorchies, Emilie Caron, Julie Charton, Emmanuelle Vallez, Benoit Deprez, Jean-Sébastien Annicotte, Sophie Lestavel, Anne Tailleux, Christophe Magnan, Bart Staels, and Kadiombo Bantubungi
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FXR ,brain ,hypothalamus ,energy homeostasis ,brown adipose tissue ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The nuclear bile acid (BA) receptor farnesoid X receptor (FXR) is a major regulator of metabolic/energy homeostasis in peripheral organs. Indeed, enterohepatic-expressed FXR controls metabolic processes (BA, glucose and lipid metabolism, fat mass, body weight). The central nervous system (CNS) regulates energy homeostasis in close interaction with peripheral organs. While FXR has been reported to be expressed in the brain, its function has not been studied so far. We studied the role of FXR in brain control of energy homeostasis by treating wild-type and FXR-deficient mice by intracerebroventricular (ICV) injection with the reference FXR agonist GW4064. Here we show that pharmacological activation of brain FXR modifies energy homeostasis by affecting brown adipose tissue (BAT) function. Brain FXR activation decreases the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and consequently the sympathetic tone. FXR activation acts by inhibiting hypothalamic PKA-CREB induction of TH expression. These findings identify a function of brain FXR in the control of energy homeostasis and shed new light on the complex control of energy homeostasis by BA through FXR.
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- 2022
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5. The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids
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Alexis Boulinguiez, Jean-Sébastien Annicotte, Laura Butruille, Anne Tailleux, Olivier Briand, Mohamed-Sami Trabelsi, Laure B. Bindels, Emilie Dorchies, Simon Peschard, Véronique Touche, Sandrine Caron, Emmanuelle Vallez, Sophie Lestavel, Sarah Ducastel, Steve Lancel, Oscar Chávez-Talavera, Nathalie M. Delzenne, Kadiombo Bantubungi, Bart Staels, Margaux Nawrot, UCL - SSS/LDRI - Louvain Drug Research Institute, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Metabolism and Nutrition Research Group [Bruxelles, Belgique], Louvain Drug Research Institute [Bruxelles, Belgique] (LDRI), Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), This work was supported by grants from 'European Genomic Institute for Diabetes' (E.G.I.D., ANR-10-LABX-46), European Commission and Agence Nationale pour la Recherche (ANR-FXREn). B.S. holds a 'European Research Council advanced Grant' (694717). A.B., M.N., O.C.T. and M.S.T. received a PhD fellowship from the French Ministry of Research., ANR-11-BSV1-0032,FXRen,Rôle du récepteur nucléaire Farnesoid X Receptor (FXR) dans l'homéostasie énergétique(2011), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Louvain Drug Research Institute [Bruxelles, Belgique], Université Catholique de Louvain (UCL)-Université Catholique de Louvain (UCL), Bodescot, Myriam, BLANC - Rôle du récepteur nucléaire Farnesoid X Receptor (FXR) dans l'homéostasie énergétique - - FXRen2011 - ANR-11-BSV1-0032 - BLANC - VALID, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M)
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Male ,0301 basic medicine ,medicine.medical_specialty ,Colon ,medicine.drug_class ,Receptors, Cytoplasmic and Nuclear ,lcsh:Medicine ,Incretin ,030209 endocrinology & metabolism ,Enteroendocrine cell ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Article ,Receptors, G-Protein-Coupled ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Nuclear receptors ,Glucagon-Like Peptide 1 ,Internal medicine ,medicine ,Animals ,Secretion ,Gastrointestinal hormones ,lcsh:Science ,Receptor ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Mice, Knockout ,Multidisciplinary ,Bile acid ,Chemistry ,Microbiota ,lcsh:R ,digestive, oral, and skin physiology ,Endocrine system and metabolic diseases ,Nutrient signalling ,Fatty Acids, Volatile ,Glucagon-like peptide-1 ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Nuclear receptor ,Preclinical research ,lcsh:Q ,Farnesoid X receptor - Abstract
The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.
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- 2020
6. Farnesoid X Receptor and Its Ligands Inhibit the Function of Platelets
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Marfoua S. Ali, David Bishop-Bailey, Neline Kriek, Gagan D. Flora, Olivier Molendi-Coste, David Dombrowicz, Sakthivel Vaiyapuri, Alexander P. Bye, Parvathy Sasikumar, Amanda J. Unsworth, Jonathan M. Gibbins, Tanya Sage, Bart Staels, Leonardo A. Moraes, and Emilie Dorchies
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0301 basic medicine ,medicine.medical_specialty ,Integrin ,Fibrinogen binding ,030204 cardiovascular system & hematology ,Biology ,G protein-coupled bile acid receptor ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,biology.protein ,Platelet aggregation inhibitor ,Platelet ,Farnesoid X receptor ,Platelet activation ,Signal transduction ,Cardiology and Cardiovascular Medicine - Abstract
Objective— Although initially seemingly paradoxical because of the lack of nucleus, platelets possess many transcription factors that regulate their function through DNA-independent mechanisms. These include the farnesoid X receptor (FXR), a member of the superfamily of ligand-activated transcription factors, that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6α-ethyl-chenodeoxycholic acid, modulate platelet activation nongenomically. Approach and Results— FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization, secretion, fibrinogen binding, and aggregation. Exposure to FXR ligands also reduced integrin α IIb β 3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cyclic guanosine monophosphate levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the nongenomic actions of these ligands to the FXR. Conclusions— This study provides support for the ability of FXR ligands to modulate platelet activation. The atheroprotective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for the prevention of atherothrombotic disease.
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- 2016
7. Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes.: Transrepression of ChREBP by FXR
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Philippe Lefebvre, Olivier Briand, Fleur Lien, Hélène Dehondt, Emilie Dorchies, Catherine Postic, Sandrine Caron, Bertrand Cariou, Bart Staels, Maheul Ploton, Carolina Huaman Samanez, Julie Dumont, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut 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), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), This work was supported by Grants from the EU Grant HEPADIP (N° 018734), the Region Nord-Pas-de-Calais/FEDER, the Agence Nationale de la Recherche (No. 11 BSV1 032 01) and 'European Genomic Institute for Diabetes' (E.G.I.D., ANR-10-LABX-46)., Récepteurs nucléaires, maladies cardiovasculaires et diabète ( EGID ), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut Cochin ( 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 ), unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de recherche de l'institut du thorax (ITX-lab), 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)
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Sialoglycoproteins ,Pyruvate Kinase ,Receptors, Cytoplasmic and Nuclear ,Biology ,Cell Line ,Histones ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Glucose homeostasis ,Animals ,Humans ,Nuclear Receptor Co-Repressor 2 ,p300-CBP Transcription Factors ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Carbohydrate-responsive element-binding protein ,Promoter Regions, Genetic ,Molecular Biology ,Transcription factor ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Binding Sites ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Lysine ,Cell Biology ,Articles ,G protein-coupled bile acid receptor ,Peptide Fragments ,Hepatocyte nuclear factors ,Protein Transport ,Glucose ,Biochemistry ,Gene Expression Regulation ,Hepatocyte Nuclear Factor 4 ,Liver ,030220 oncology & carcinogenesis ,Hepatocytes ,Farnesoid X receptor ,Glycolysis ,Pyruvate kinase - Abstract
International audience; The glucose-activated transcription factor carbohydrate response element binding protein (ChREBP) induces the expression of hepatic glycolytic and lipogenic genes. The farnesoid X receptor (FXR) is a nuclear bile acid receptor controlling bile acid, lipid, and glucose homeostasis. FXR negatively regulates hepatic glycolysis and lipogenesis in mouse liver. The aim of this study was to determine whether FXR regulates the transcriptional activity of ChREBP in human hepatocytes and to unravel the underlying molecular mechanisms. Agonist-activated FXR inhibits glucose-induced transcription of several glycolytic genes, including the liver-type pyruvate kinase gene (L-PK), in the immortalized human hepatocyte (IHH) and HepaRG cell lines. This inhibition requires the L4L3 region of the L-PK promoter, known to bind the transcription factors ChREBP and hepatocyte nuclear factor 4α (HNF4α). FXR interacts directly with ChREBP and HNF4α proteins. Analysis of the protein complex bound to the L4L3 region reveals the presence of ChREBP, HNF4α, FXR, and the transcriptional coactivators p300 and CBP at high glucose concentrations. FXR activation does not affect either FXR or HNF4α binding to the L4L3 region but does result in the concomitant release of ChREBP, p300, and CBP and in the recruitment of the transcriptional corepressor SMRT. Thus, FXR transrepresses the expression of genes involved in glycolysis in human hepatocytes.
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- 2013
8. Farnesoid x receptor deficiency improves glucose homeostasis in mouse models of obesity.: FXR-deficiency improves glucose metabolism in obesity
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Iuliana Popescu, Theo H. van Dijk, Vidya Velagapudi, Bertrand Cariou, F Anthony San Lucas, Hélène Duez, Sandrine Caron, Matej Orešič, Julie Dumont, Janne Prawitt, Mehdi Daoudi, Sophie Lestavel, Emilie Dorchies, Frank J. Gonzalez, Mouaadh Abdelkarim, Johanna H.M. Stroeve, Folkert Kuipers, Emmanuel Bouchaert, Bart Staels, Center for Liver, Digestive and Metabolic Diseases (CLDM), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Pediatrics, University of Groningen and University Medical Center Groningen-Center for Liver, Digestive and Metabolic Diseases, Technical Research Centre of Finland, VTT Technical Research Centre of Finland (VTT), Laboratory of metabolism, Center for Cancer Research-National Institute of Health (NIH), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), and This study was supported by the EU Grant HEPADIP (N° 018734), the Agence Nationale de la Recherche (No.A05056GS) and COST (Action BM0602).
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Male ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,CARBOHYDRATE-METABOLISM ,Adipose tissue ,Mice, Obese ,Receptors, Cytoplasmic and Nuclear ,Weight Gain ,TRIGLYCERIDE LEVELS ,triglyceride metabolism ,bile acid sequestrants ,ACTIVATION ,0302 clinical medicine ,energy metabolism ,Glucose homeostasis ,Homeostasis ,Insulin ,2. Zero hunger ,Hypertriglyceridemia ,0303 health sciences ,BILE-ACIDS ,INSULIN-RESISTANCE ,ADIPOCYTE DIFFERENTIATION ,Adipose Tissue ,FXR ,030220 oncology & carcinogenesis ,SENSITIVITY ,medicine.medical_specialty ,Carbohydrate metabolism ,Biology ,Bile Acids and Salts ,03 medical and health sciences ,Insulin resistance ,SDG 3 - Good Health and Well-being ,HYPERGLYCEMIA ,Internal medicine ,Internal Medicine ,medicine ,glucose homeostasis ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Obesity ,030304 developmental biology ,bile acids ,Lipid metabolism ,medicine.disease ,Lipid Metabolism ,Disease Models, Animal ,MICE ,Endocrinology ,Glucose ,Metabolism ,Farnesoid X receptor ,Insulin Resistance - Abstract
OBJECTIVE Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed. RESEARCH DESIGN AND METHODS Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity. RESULTS FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism. CONCLUSIONS Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis.
- Published
- 2011
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