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1. CRISPR/Cas9-mediated inactivation of the phosphatase activity of soluble epoxide hydrolase prevents obesity and cardiac ischemic injury

Author

Matthieu Leuillier, Thomas Duflot, Séverine Ménoret, Hind Messaoudi, Zoubir Djerada, Déborah Groussard, Raphaël G.P. Denis, Laurence Chevalier, Ahmed Karoui, Baptiste Panthu, Pierre-Alain Thiébaut, Isabelle Schmitz-Afonso, Séverine Nobis, Cynthia Campart, Tiphaine Henry, Camille Sautreuil, Serge H. Luquet, Olivia Beseme, Catherine Féliu, Hélène Peyret, Lionel Nicol, Jean-Paul Henry, Sylvanie Renet, Paul Mulder, Debin Wan, Laurent Tesson, Jean-Marie Heslan, Angéline Duché, Sébastien Jacques, Frédéric Ziegler, Valéry Brunel, Gilles J.P. Rautureau, Christelle Monteil, Jean-Luc do Rego, Jean-Claude do Rego, Carlos Afonso, Bruce Hammock, Anne-Marie Madec, Florence Pinet, Vincent Richard, Ignacio Anegon, Christophe Guignabert, Christophe Morisseau, and Jérémy Bellien

Subjects
Soluble epoxide hydrolase, Lipid phosphatase, CRISPR-Cas9, Thermogenesis, Obesity, Cardiac ischemic injury, Medicine (General), R5-920, Science (General), Q1-390
Abstract

Introduction: Although the physiological role of the C-terminal hydrolase domain of the soluble epoxide hydrolase (sEH-H) is well investigated, the function of its N-terminal phosphatase activity (sEH-P) remains unknown. Objectives: This study aimed to assess in vivo the physiological role of sEH-P. Methods: CRISPR/Cas9 was used to generate a novel knock-in (KI) rat line lacking the sEH-P activity. Results: The sEH-P KI rats has a decreased metabolism of lysophosphatidic acids to monoacyglycerols. KI rats grew almost normally but with less weight and fat mass gain while insulin sensitivity was increased compared to wild-type rats. This lean phenotype was more marked in males than in female KI rats and mainly due to decreased food consumption and enhanced energy expenditure. In fact, sEH-P KI rats had an increased lipolysis allowing to supply fatty acids as fuel to potentiate brown adipose thermogenesis under resting condition and upon cold exposure. The potentiation of thermogenesis was abolished when blocking PPARγ, a nuclear receptor activated by intracellular lysophosphatidic acids, but also when inhibiting simultaneously sEH-H, showing a functional interaction between the two domains. Furthermore, sEH-P KI rats fed a high-fat diet did not gain as much weight as the wild-type rats, did not have increased fat mass and did not develop insulin resistance or hepatic steatosis. In addition, sEH-P KI rats exhibited enhanced basal cardiac mitochondrial activity associated with an enhanced left ventricular contractility and were protected against cardiac ischemia–reperfusion injury. Conclusion: Our study reveals that sEH-P is a key player in energy and fat metabolism and contributes together with sEH-H to the regulation of cardiometabolic homeostasis. The development of pharmacological inhibitors of sEH-P appears of crucial importance to evaluate the interest of this promising therapeutic strategy in the management of obesity and cardiac ischemic complications.

Published
2023
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2. Alterations of proteome, mitochondrial dynamic and autophagy in the hypothalamus during activity-based anorexia

Author

Séverine Nobis, Alexis Goichon, Najate Achamrah, Charlène Guérin, Saida Azhar, Philippe Chan, Aline Morin, Christine Bôle-Feysot, Jean Claude do Rego, David Vaudry, Pierre Déchelotte, Liliana Belmonte, and Moïse Coëffier

Subjects
Medicine, Science
Abstract

Abstract Restrictive anorexia nervosa is associated with reduced eating and severe body weight loss leading to a cachectic state. Hypothalamus plays a major role in the regulation of food intake and energy homeostasis. In the present study, alterations of hypothalamic proteome and particularly of proteins involved in energy and mitochondrial metabolism have been observed in female activity-based anorexia (ABA) mice that exhibited a reduced food intake and a severe weight loss. In the hypothalamus, mitochondrial dynamic was also modified during ABA with an increase of fission without modification of fusion. In addition, increased dynamin-1, and LC3II/LC3I ratio signed an activation of autophagy while protein synthesis was increased. In conclusion, proteomic analysis revealed an adaptive hypothalamic protein response in ABA female mice with both altered mitochondrial response and activated autophagy.

Published
2018
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3. Effects of Bacterial CLPB Protein Fragments on Food Intake and PYY Secretion

Author

Manon Dominique, Nicolas Lucas, Romain Legrand, Illona-Marie Bouleté, Christine Bôle-Feysot, Camille Deroissart, Fatima Léon, Séverine Nobis, Jean-Claude do Rego, Grégory Lambert, and Pierre Déchelotte

Subjects
caseinolytic peptidase B, fragments, food intake, peptide YY, in vivo, Nutrition. Foods and food supply, TX341-641
Abstract

CLPB (Caseinolytic peptidase B) protein is a conformational mimetic of α-MSH, an anorectic hormone. Previous in vivo studies have already shown the potential effect of CLPB protein on food intake and on the production of peptide YY (PYY) by injection of E. coli wild type (WT) or E. coli ΔClpB. However, until now, no study has shown its direct effect on food intake. Furthermore, this protein can fragment naturally. Therefore, the aim of this study was (i) to evaluate the in vitro effects of CLPB fragments on PYY production; and (ii) to test the in vivo effects of a CLPB fragment sharing molecular mimicry with α-MSH (CLPB25) compared to natural fragments of the CLPB protein (CLPB96). To do that, a primary culture of intestinal mucosal cells from male Sprague–Dawley rats was incubated with proteins extracted from E. coli WT and ΔCLPB after fragmentation with trypsin or after a heat treatment of the CLPB protein. PYY secretion was measured by ELISA. CLPB fragments were analyzed by Western Blot using anti-α-MSH antibodies. In vivo effects of the CLPB protein on food intake were evaluated by intraperitoneal injections in male C57Bl/6 and ob/ob mice using the BioDAQ® system. The natural CLPB96 fragmentation increased PYY production in vitro and significantly decreased cumulative food intake from 2 h in C57Bl/6 and ob/ob mice on the contrary to CLPB25. Therefore, the anorexigenic effect of CLPB is likely the consequence of enhanced PYY secretion.

Published
2021
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4. Changes in Microbiota and Bacterial Protein Caseinolytic Peptidase B During Food Restriction in Mice: Relevance for the Onset and Perpetuation of Anorexia Nervosa

Author

Manon Dominique, Romain Legrand, Marie Galmiche, Saïda Azhar, Camille Deroissart, Charlène Guérin, Jean-Luc do Rego, Fatima Leon, Séverine Nobis, Grégory Lambert, Nicolas Lucas, and Pierre Déchelotte

Subjects
anorexia, food restriction, clpb, microbiota, enterobacteriaceae, Nutrition. Foods and food supply, TX341-641
Abstract

Microbiota contributes to the regulation of eating behavior and might be implicated in the pathophysiology of anorexia nervosa. ClpB (Caseinolytic peptidase B) protein produced mainly by the Enterobacteriaceae family has been identified as a conformational mimetic of α-MSH, which could result in similar anorexigenic effects. The aim of this study was to highlight the role of the microbiome and the ClpB protein in deregulation and self-maintenance of anorexia pathology. Male C57Bl/6 mice were undergone to the ABA (Activity-Based Anorexia) protocol: after 5 days of acclimatization, both ABA and LFA (Limited Food Access) mice had progressively limited access to food until D17. At the end of protocol, the plasma ClpB concentration and Enterobacteriaceae DNA in colonic content were measured. As expected, dietary restriction induced lost weight in LFA and ABA mice. At D10, colonic permeability and plasma concentration of the ClpB protein were significantly increased in LFA and ABA mice vs. controls. At D17, plasma concentration of ClpB was increased in LFA and ABA mice and, it was correlated with proportion of Enterobacteriaceae in the faeces. These abnormally high ClpB concentrations and all associated factors, and therefore might contribute to the initiation and/or perpetuation of anorexia nervosa by interfering with satiety signaling.

Published
2019
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5. Glutamine, but not Branched-Chain Amino Acids, Restores Intestinal Barrier Function during Activity-Based Anorexia

Author

Clément L’Huillier, Marine Jarbeau, Najate Achamrah, Liliana Belmonte, Asma Amamou, Séverine Nobis, Alexis Goichon, Emmeline Salameh, Wafa Bahlouli, Jean-Luc do Rego, Pierre Déchelotte, and Moïse Coëffier

Subjects
glutamine, Branched-chain amino acids, Activity-Based Anorexia, Intestinal permeability, Nutrition. Foods and food supply, TX341-641
Abstract

Background: During activity-based anorexia (ABA) in mice, enhanced paracellular permeability and reduced protein synthesis have been shown in the colon while the gut−brain axis has received increasing attention in the regulation of intestinal and mood disorders that frequently occur during anorexia nervosa, a severe eating disorder for which there is no specific treatment. In the present study, we assessed the effects of oral glutamine (Gln) or branched-chain amino acids (BCAA) supplementation during ABA to target intestinal functions, body composition and feeding behavior. Methods: C57BL/6 male mice were randomized in Control (CTRL) and ABA groups. After ABA induction, mice received, or not, either 1% Gln or 2.5% BCAA (Leu, Ile, Val) for one week in drinking water. Results: Neither Gln nor BCAA supplementation affected body weight and body composition, while only Gln supplementation slightly increased food intake. ABA mice exhibited increased paracellular permeability and reduced protein synthesis in the colonic mucosa. Oral Gln restored colonic paracellular permeability and protein synthesis and increased the mucin-2 mRNA level, whereas BCAA did not affect colonic parameters. Conclusion: In conclusion, oral Gln specifically improves colonic response during ABA. These data should be further confirmed in AN patients.

Published
2019
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6. CRISPR/Cas9-mediated inactivation of the phosphatase activity of soluble epoxide hydrolase prevents obesity and cardiac ischemic injury

Author

Matthieu Leuillier, Thomas Duflot, Séverine Ménoret, Hind Messaoudi, Zoubir Djerada, Déborah Groussard, Raphaël G.P. Denis, Laurence Chevalier, Ahmed Karoui, Baptiste Panthu, Pierre-Alain Thiébaut, Isabelle Schmitz-Afonso, Séverine Nobis, Cynthia Campart, Tiphaine Henry, Camille Sautreuil, Serge H. Luquet, Olivia Beseme, Catherine Féliu, Hélène Peyret, Lionel Nicol, Jean-Paul Henry, Sylvanie Renet, Paul Mulder, Debin Wan, Laurent Tesson, Jean-Marie Heslan, Angéline Duché, Sébastien Jacques, Frédéric Ziegler, Valéry Brunel, Gilles J.P. Rautureau, Christelle Monteil, Jean-Luc do Rego, Jean-Claude do Rego, Carlos Afonso, Bruce Hammock, Anne-Marie Madec, Florence Pinet, Vincent Richard, Ignacio Anegon, Christophe Guignabert, Christophe Morisseau, Jérémy Bellien, Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé - François Bonamy, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Groupe de physique des matériaux (GPM), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Aliments Bioprocédés Toxicologie Environnements (ABTE), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département de Pathologie [CHU Rouen], CHU Rouen, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), 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), University of California [Davis] (UC Davis), University of California (UC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre de RMN à très hauts champs de Lyon (CRMN), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pôle des Cardiopathies Congénitales du Nouveau-Né à L'adulte - Centre Constitutif Cardiopathies Congénitales Complexes M3C, Groupe Hospitalier Paris Saint-Joseph, Hôpital Marie-Lannelongue, Inserm U999, Université Paris-Saclay, Luquet, Serge, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), and ANR-16-CE17-0012,SAPHIR,Impact de la modulation des activités enzymatiques de l'époxyde hydrolase soluble sur l'hypertension pulmonaire et la dysfonction ventriculaire droite lors de l'insuffisance cardiaque expérimentale et humaine(2016)

Subjects
Male, Heart Diseases, [SDV]Life Sciences [q-bio], Cardiovascular, Lipid phosphatase, 2.1 Biological and endogenous factors, Animals, Obesity, Aetiology, Metabolic and endocrine, Nutrition, Epoxide Hydrolases, Multidisciplinary, Thermogenesis, Phosphoric Monoester Hydrolases, Rats, [SDV] Life Sciences [q-bio], Soluble epoxide hydrolase, Heart Injuries, Reperfusion Injury, Female, CRISPR-Cas9, CRISPR-Cas Systems, Insulin Resistance, Lysophospholipids, Cardiac ischemic injury
Abstract

IntroductionAlthough the physiological role of the C-terminal hydrolase domain of the soluble epoxide hydrolase (sEH-H) is well investigated, the function of its N-terminal phosphatase activity (sEH-P) remains unknown.ObjectivesThis study aimed to assess in vivo the physiological role of sEH-P.MethodsCRISPR/Cas9 was used to generate a novel knock-in (KI) rat line lacking the sEH-P activity.ResultsThe sEH-P KI rats has a decreased metabolism of lysophosphatidic acids to monoacyglycerols. KI rats grew almost normally but with less weight and fat mass gain while insulin sensitivity was increased compared to wild-type rats. This lean phenotype was more marked in males than in female KI rats and mainly due to decreased food consumption and enhanced energy expenditure. In fact, sEH-P KI rats had an increased lipolysis allowing to supply fatty acids as fuel to potentiate brown adipose thermogenesis under resting condition and upon cold exposure. The potentiation of thermogenesis was abolished when blocking PPARγ, a nuclear receptor activated by intracellular lysophosphatidic acids, but also when inhibiting simultaneously sEH-H, showing a functional interaction between the two domains. Furthermore, sEH-P KI rats fed a high-fat diet did not gain as much weight as the wild-type rats, did not have increased fat mass and did not develop insulin resistance or hepatic steatosis. In addition, sEH-P KI rats exhibited enhanced basal cardiac mitochondrial activity associated with an enhanced left ventricular contractility and were protected against cardiac ischemia-reperfusion injury.ConclusionOur study reveals that sEH-P is a key player in energy and fat metabolism and contributes together with sEH-H to the regulation of cardiometabolic homeostasis. The development of pharmacological inhibitors of sEH-P appears of crucial importance to evaluate the interest of this promising therapeutic strategy in the management of obesity and cardiac ischemic complications.

Published
2021

7. A role for intestinal TLR4-driven inflammatory response during activity-based anorexia

Author

Liliana, Belmonte, Najate, Achamrah, Séverine, Nobis, Charlène, Guérin, Gaëtan, Riou, Christine, Bôle-Feysot, Olivier, Boyer, Vincent, Richard, Jean Claude Do, Rego, Pierre, Déchelotte, Alexis, Goichon, Moïse, Coëffier, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Service Commun d'Analyse Comportementale (SCAC), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de nutrition [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and douville, sabine

Subjects
Mice, Knockout, Colon, Hypothalamus, Article, Anorexia, Gastroenteritis, Mice, Inbred C57BL, Toll-Like Receptor 4, Disease Models, Animal, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Physical Conditioning, Animal, Weight Loss, Animals, Cytokines, Female, Intestinal Mucosa, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, ComputingMilieux_MISCELLANEOUS, Signal Transduction
Abstract

Anorexia nervosa (AN) is associated with low-grade systemic inflammation and altered gut microbiota. However, the molecular origin of the inflammation remains unknown. Toll-like receptors are key regulators of innate immune response and their activation seems also to be involved in the control of food intake. We used activity-based anorexia (ABA) model to investigate the role of TLR4 and its contribution in anorexia-associated low-grade inflammation. Here, we found that ABA affected early the intestinal inflammatory status and the hypothalamic response. Indeed, TLR4 was upregulated both on colonic epithelial cells and intestinal macrophages, leading to elevated downstream mucosal cytokine production. These mucosal changes occurred earlier than hypothalamic changes driving to increased levels of IL-1β and IL-1R1 as well as increased levels of plasma corticosterone. Paradoxically, TLR4-deficient mice exhibited greater vulnerability to ABA with increased mortality rate, suggesting a major contribution of TLR4-mediated responses during ABA-induced weight loss.

Published
2016

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