A Novel Strategy for the Treatment of Obesity Using the Small Molecule ABX300, a Modulator of the LMNA Gene Splicing Celia Lopez Herrera

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A Novel Strategy for the Treatment of Obesity Using the Small Molecule ABX300, a Modulator of the LMNA Gene Splicing Celia Lopez Herrera A novel strategy for the treatment of Obesity using the small molecule ABX300, a modulator of the LMNA gene splicing Celia Lopez Herrera To cite this version: Celia Lopez Herrera. A novel strategy for the treatment of Obesity using the small molecule ABX300, a modulator of the LMNA gene splicing. Human health and pathology. Université Montpellier, 2015. English. NNT : 2015MONTT048. tel-01549093 HAL Id: tel-01549093 https://tel.archives-ouvertes.fr/tel-01549093 Submitted on 28 Jun 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Délivré par l’Université de Montpellier Préparée au sein de l’école doctorale CBS2 n°168 Sciences Chimiques et Biologiques pour la Santé Et de l’unité de recherche CNRS-UMR5535 Spécialité : Biologie moléculaire, Biologie cellulaire Présentée par Celia LÓPEZ HERRERA "Une Nouvelle stratégie pour le traitement de l'obésité en utilisant ABX300, une molé cule modulatrice de l’épissage du gène LMNA " Soutenue le 17 Décembre 2015 devant le jury composé de Anne-Dominique LAJOIX, PU, Université de Montpellier Présidente Philippe VALET, PU, Université de Toulouse Rapporteur Ez-Zoubir AMRI, DR2, Université de Nice Rapporteur François CASAS, DR2, Université de Montpellier Examinateur Ramón GOMIS, PU, Universidad de Barcelona Examinateur Jamal TAZI, PU, Université de Montpellier Directeur de thèse RESUME EN FRANÇAIS Synthèse du mémoire en français Synthèse du mémoire Introduction I. Le tissu adipeux et l'obésité La perception du tissu adipeux a considérablement changé au cours de ces dernières décennies avec la spectaculaire augmentation de l'incidence de l'obésité et sa morbidité associée. Au niveau mondial, mais plus particulièrement dans les pays industrialisés, l'obésité compte à présent parmi l’ une des plus grandes préoccupations de santé publique. Même si cette maladie chronique a une étiologie multifactorielle, elle peut être simplement définie par une augmentation de l'accumulation de la graisse corporelle. Chez la majorité des patients, l ’obésité est la conséquence d’un apport énergétique supérieur à la dépense. Peu de thérapies médicales sont actuellement reconnues et elles visent en général un ou plusieurs des mécanismes suivants: prévention de l'absorption des graisses, diminution de l'appétit et augmentation du métabolisme corporel. Pour étudier les mécanismes liés à l’obésité, plusieurs modèles de rongeurs sont disponibles, permettant d’être en mesure d’émettre des hypothèses applicables à l’homme . Parmi ces modèles animaux ils existent par exemple des souris présentant des altérations concernant la leptine, une hormone qui régule les réserves de graisses dans l'organisme et l'appétit, parfois dite « hormone de la satiété ». Les souris ob/ob , sont mutées génétiquement au niveau du gène codant la leptine; et les souris db/db sont mutées au niveau du récepteur à la leptine. Très utilisés aussi ce sont les souris DIO (diet-induced obesity), chez lesquelles l’obésité est induite par un régime alimentaire riche en lipides. Le tissu adipeux est susceptible aux changements diététiques, en effet il est sensible à l'insuline sécrétée suite aux repas, ainsi qu’à l’adrénaline produite lors d’un stress. De plus , un bon fonctionnement du système nerveux est requis pour détecter l'état des réserves énergétiques et faire correspondre les apports avec les dépenses. Des réponses métaboliques et comportementales sont ainsi Synthèse du mémoire en français déclenchées, visant à maintenir l'équilibre énergétique. Dans l'ensemble, cet équilibre est sensible à divers facteurs, y compris des hormones, des neurotransmetteurs et des facteurs psychologiques et culturels. Les adipocytes sont équipés de la machinerie biochimique nécessaire pour fonctionner efficacement en tant que site de stockage du carburant de l'organisme. Pour ce faire, ils sont aussi bien responsables de la conversion des acides gras libres en triglycérides permettant la lipogénèse (stockage des corps gras), que du processus inverse, la lipolyse (libération des corps gras). Outre ces deux fonctions fondamentales, le tissu adipeux est crucial pour l'activité du système endocrinien via sa fonction sécrétrice, qui est indispensable pour le maintien de l'homéostasie dans l’organisme. Des peptides et autres facteurs agissant de façon endocrine ou paracrine (adipokines/adipocytokines), sont libérés par ce tissu et/ou par sa fraction stroma vasculaire, et vont exercer des effets métaboliques très variés. Parmi ceux-ci on compte des adipocytokines pro- inflammatoires qu’on trouve augmentées en relation avec l’obésité tel que la leptine, la resistine, le TNF-α, l’IL -6 et le PAI-1; ainsi que d’autres adipokines comme l’adiponectine, l’apeline, l’adipsine et le FGF21. Les deux principaux types de tissu adipeux sont le blanc et le brun. Typiquement, le tissu adipeux blanc représente environ 20% du poids corporel chez l’homme et 28% chez la femme (Thompson et al., 2012) mais chez les personnes obèses, il peut représenter jus qu’à 80% de ce poids. L'obésité est accompagnée d'une hausse généralisée des dépôts de tissu adipeux blanc en raison de l'hyperplasie (augmentation du nombre des adipocytes) et de l'hypertrophie (augmentation de la taille des adipocytes) (Dulloo et al., 2010). Les caractéristiques principales des adipocytes blancs sont le stockage d’excès d'énergie sous forme triglycérides dans de grosses gouttelettes uniloculaires, et la libération de cette énergie sous la forme d'acides gras libres dans des situations de besoin énergétique, comme le jeun, ou en réponse à un stimulus tel que la sécrétion d’adrénaline. De leur côté, les adipocytes bruns stockent des triglycérides sous forme multiloculaire, de sorte qu’ils puissent être rapidement utilisés comme combustible pour la production de chaleur à travers un processus biochimique, Synthèse du mémoire en français le "découplage" mitochondrial de la phosphorylation oxydative des acides gras libres (Sethi and Vidal-Puig, 2007). Chez les mammifères, le tissu adipeux brun peut dissiper l’énergie lipidique sous forme de chaleur dans un processus appelé thermogenèse sans frisson (Bartelt and Heeren, 2014). En effet les adipocytes bruns expriment au niveau de leur membrane mitochondriale interne une protéine de 32 kDa appelée UCP1 (protéine de découplage 1) permettant une dissipation du gradient électrochimique de protons généré par la respiration sous forme de chaleur (Cannon, 2004). Le tissu adipeux brun est donc unique en raison de sa fonction dans la thermogénèse comme forme de dépense énergétique, cette énorme capacité thermogénique apportant une contribution substantielle au m étabolisme énergétique de l’organisme. Par ailleurs, il peut être distingué du tissu adipeux blanc morphologiquement par une vascularisation plus riche et une plus grande densité mitochondriale. Récemment, une troisième catégorie d’adipocytes distincts des adipocytes blancs et bruns a été décrite. Ce sont des adipocytes bruns inductibles, qui ont été nommés des « adipocytes beiges/brite » (Giralt and Villarroya, 2013). Les adipocytes beiges sont notamment présents au sein du tissu adipeux blanc. Leur processus d’activation est décrit comme le '' brunissement ''. Ce phénomène est caractérisé par l'expression d'UCP1 et il entraîne des effets métaboliques bénéfiques. Le fr oid ainsi que l’activation de la voie β3 -adrénergique ont été reconnues entre autres comme activateurs du brunissage. Finalement, dès leur développement, les trois types d’adipocytes sont bien distincts avec une expression différentielle de nombreux gènes (Baboota et al., 2015). L’utilisation de différentes lignées cellulaires (3T3 -L1, 3T3F442A, C3H10T1/2, préadipocytes bruns, etc.) a permis récemment de mettre à jour le contrôle transcriptionnel au cours de la différenciation adipocytaire ainsi que les fonctions des adipocytes. L'une des caractéristiques qui permettent de mieux distinguer ces trois types d’adipocytes est la quantité de mitochondries. II. Les Mitochondries et l'homéostasie énergétique Une fonction mitochondriale normale est nécessaire et requise pour la préservation d’un équilibre approprié entre le stockage et la dépense énergétique. Un excès de nutriments mène à des dysfonctionnements Synthèse du mémoire en français mitochondriaux, qui sont accompagnés d’effets indirects sur le métabolisme des lipides et du glucose (Bournat et Brown, 2010). Les mitochondries sont des organelles qui fournissent environ 90% de l'énergie requise pour le bon fonctionnement de la cellule eucaryote (Tao et al., 2014 ). L’énergie fournie par le glucose et les lipides contenus dans les aliments est transformée en ATP (adénosine-5′ -triphosphate), de sorte qu’elle puisse être utilisée par la cellule. Ceci est possible grâce aux deux processus que sont la glycolyse et l’ oxydation des acides gras. La glycolyse est un processus anaérobie transformant le glucose en pyruvate avec une faible production d'énergie comparativement à la respiration aérobie. Le processus d’oxydation des acides gras se caractérise quant à lui par une série de réactions diminuant la taille des acides
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