Darcel, Nicolas (2005) La viscérosensibilité chimique intestinale: Mécanismes et implications dans le contrôle de la prise alimentaire chez le rat. PhD thesis Nutrition animale, UFR biologie et nutrition humaine, INAPG 2005INAP0010 p.250.

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Abstract

INTRODUCTION: Although, the implication of intestinal chemosensitivity in the

control of food intake is now widely accepted, its precise mechanisms and its modalities

of communication with the central nervous system remain poorly understood.

OBJECTIVE: the aim of this study was to refine our understanding of nutrient detection

within the intestine and to determine the involvement of vagal pathways in the transfer

of visceral information from the gastrointestinal tract to the brain. RESULTS: the present

study supports the hypothesis proposing that the intestine can be considered also as a

sensory organ. It also appeared that the vagus nerve does play a role in transmitting

visceral information to the brain. CONCLUSIONS: Vagally mediated intestinal

chemosensitivity should be regarded as a sensory system having a strong influence on

food intake control. Understanding its implications in energy homeostatic control will

undoubtedly lead to develop new therapies to fight the present obesity epidemics.

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Table of content

Table des matières - 5

Table des illustrations et figures - 10

Enjeux - 13

- 13

De l’intérêt de comprendre les bases neurophysiologiques du comportement alimentaire - 13

Principes et fondements de la science du comportement alimentaire - 14

L’obésité, un problème global majeur de santé publique - 14

Vers une lutte thérapeutique contre l’obésité - 15

Introduction - 16

Le comportement alimentaire, définitions, principes de base, approche expérimentale et

mécanismes biologiques de contrôle - 16

Régulation du poids corporel et comportement alimentaire - 17

Définitions du comportement alimentaire - 20

Les différentes composantes du comportement alimentaire - 20

Principes de base du contrôle du comportement alimentaire - 23

Le contrôle du comportement alimentaire - 23

Le comportement alimentaire est influencé par de nombreux facteurs - 25

Deux déterminants principaux dirigent le comportement alimentaire - 27

Les mécanismes du contrôle du comportement alimentaire - 28

L’hypothalamus: le chef d’orchestre du comportement alimentaire - 28

Présentation de l’hypothalamus - 29

Le système mélanocortine central - 32

Le système mélanocortine central hypothalamique - 33

Le système mélanocortine central hypothalamique est influencé par la disponibilité en énergie et par les

informations émises au cours des repas - 36

Gestion des réserves en énergie à long terme: influence de la disponibilité en énergie sur le fonctionnement

du système mélanocortine central hypothalamique: exemple de la leptine et de l’insuline - 36

Action immédiate de signaux digestifs sur le système mélanocortine central hypothalamique pendant la

digestion: exemple de la ghréline - 39

Le système mélanocortine central hypothalamique, un processeur central du comportement alimentaire - 39

Le système mélanocortine central du tronc cérébral - 40

L’axe tube digestif-cerveau et le contrôle de l’ ingestion pendant la digestion - 46

Le tube digestif sous surveillance - 46

L’innervation du tractus digestif - 48

La détection des nutriments dans l’intestin et la génération de signaux anorexigènes depuis le tube digestif . . . 54

Principes généraux de la détection de macronutriments dans la lumière intestinale - 54

Exemple de la CCK - 55

Présentation des études - 57

Enjeux: Intéroception intestinale et comportement alimentaire - 58

L’étude des mécanismes biologiques précis de la détection des macronutriments dans l’intestin

- 61

Implications de la sensibilité viscérale dans le contrôle de la prise alimentaire et plasticité à long

terme du système intéroceptif - 62

6

Première Partie: - 63

Mécanismes cellulaires et moléculaires responsables de la détection du glucose dans l’intestin au

cours de la digestion - 63

Introduction - 64

La détection du glucose dans l’intestin - 65

Rôle de la sérotonine - 65

Implication des transporteurs membranaires du glucose - 68

Etude 1: Caractérisation du transporteur impliqué dans la détection du glucose dans l’ingesta,

approche électrophysiologique - 69

Introduction - 69

Matériels et méthodes - 71

Animaux et préparations de solutions - 71

Enregistrement des décharges spontanées des afférences vagales - 72

Analyse des enregistrements - 72

Enregistrement des décharges spontanées des afférences vagales en réponse à la perfusion de glucose et de

galactose - 73

Résultats - 74

Discussion - 75

Perspectives - 76

Etude 2: Les mécanismes cellulaires responsables de l’induction de la libération de sérotonine

par les cellules entéroendocrines lors de l’action du glucose sur le transporteur de glucose

SGLT3 - 77

Introduction - 77

Biologie cellulaire de la libération de médiateurs - 77

Deux mécanismes possibles pour la libération de sérotonine induite par la présence de glucose - 78

Objectif de l’étude - 81

Présentation de la démarche expérimentale - 83

Matériel et méthodes - 83

Culture de cellules - 83

Solutions - 84

Enregistrement du potentiel transmembranaire par la technique du patch clamp - 85

Protocole expérimental - 86

Résultats - 86

Cellules de type BON - 86

Cellules de type STC1 - 86

Discussion - 90

Conclusion sur les mécanismes cellulaires de la détection du glucose dans l’intestin - 92

Deuxième Partie: - 94

Mécanismes cellulaires responsables de la détection des acides gras à chaîne longue dans

l’intestin au cours de la digestion - 94

Introduction - 95

La détection des acides gras par l’organisme - 95

Les mécanismes de détection des acides gras à chaîne longue dans l’intestin, au cours de la

digestion - 96

Apo A-IV et détection des acides gras à chaîne longue - 99

Par quelles voies l’apo A-IV influence-t-elle le comportement alimentaire et le fonctionnement digestif? . . . 100

7

Étude 3: Evaluation du rôle des afférences vagales dans la détection des acides gras à chaîne

longue - 102

- 102

Résumé de l’article - 102

Discussion - 103

Action directe ou libération de CCK - 105

De l’apo A-IV à la libération de CCK par les cellules entéroendocrines - 105

Conclusion - 106

Article: Glatzle J, Darcel N, Rechs AJ, Kalogeris TJ, Tso P and Raybould HE. Apolipoprotein A IV

stimulates duodenal vagal afferent activity to inhibit gastric motility via a CCK1 pathway . 107

Troisième Partie: - 114

Mécanismes cellulaires responsables de la détection des oligopeptides dans l’intestin au cours de

la digestion - 114

Introduction - 115

De l’intérêt de détecter la présence et la disponibilité des protéines - 115

Les stratégies mises en place par l’organisme pour s’informer de la disponibilité en protéines et/ou en acides

aminés sont nombreuses - 116

Les protéines alimentaires sont détectées lors de leur absorption dans l’intestin - 116

Les mécanismes de la détection des protéines dans l’intestin - 117

Les hypothèses proposées pour la détection des protéines dans l’intestin - 118

L’activité de PEPT1 au cours de la digestion initie-t-elle la détection des oligopeptides dans l’intestin ? - 120

Étude 4: Détermination du rôle du transporteur d’oligopeptides PEPT1 dans la détection des

oligopeptides du contenu digestif - 121

Résumé de l’étude - 121

Discussion - 121

Relation entre activité de PEPT1 et libération de CCK - 123

Comment l’activité de PEPT1 peut-elle générer un signal cellulaire ? - 123

Où est localisé PEPT1 ? - 125

Conclusion - 128

Article: Darcel NP, Liou AP, Tome D and Raybould HE. Activation of vagal afferents in the rat

duodenum by protein digests requires PepT1 - 129

Quatrième partie: - 135

Implication du nerf vague dans le contrôle de la prise alimentaire par la détection des protéines

dans l’intestin - 135

Étude 5: Effets d’un régime hyper-protéique sur l’activation des régions du système nerveux

central impliquées dans la régulation de la balance énergétique - 136

Introduction - 136

Description de l’étude - 138

Dicussion - 141

Conclusion - 142

Article: Darcel N, Fromentin G, Raybould HE, Gougis S, Gietzen DW and Tome D. Fos-positive

neurons are increased in the nucleus of the solitary tract and decreased in the ventromedial

hypothalamus and amygdala by a high-protein diet in rats - 143

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Étude 6: Participation du nerf vague à la satiété induite par les protéines alimentaires - 149

Introduction - 150

Objet de l’étude - 151

Méthodes - 151

Principes - 151

Animaux - 152

Traitement à la capsaïcine - 153

Traitement statistique - 156

Résultats - 156

Suivi des traitements - 156

Prise alimentaire - 156

Prise de poids - 157

Conclusion générale - 163

Vers une physiologie intégrative - 166

Nos résultats et les modèles que nous proposons - 167

Perspectives - 172

Annexes - 174

Annexe 1: Enregistrement de l’activité spontanée des afférences vagales à partir d’une

préparation isolée de duodénum: - 175

Annexe 2: Le patch clamp - 178

Annexe 3: Le c-fos, un marqueur de l’activation des neurones - 181

Annexe 4: Capsaïcine et excitotoxicité - 186

Annexe 5: Publications et communications - 188

Annexe 7: Glossaire - 222

Références bibliographiques - 233

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