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Le Rôle Et La Régulation Du Pyroglutamylated RF-Amide Peptide Dans Le Tissu Adipeux Lors De L’Obésité

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Le Rôle Et La Régulation Du Pyroglutamylated RF-Amide Peptide Dans Le Tissu Adipeux Lors De L’Obésité Université de Montréal Le rôle et la régulation du pyroglutamylated RF-amide peptide dans le tissu adipeux lors de l’obésité par Christian Jossart Faculté de pharmacie Thèse présentée à la Faculté de pharmacie en vue de l’obtention du grade de Philosophiae doctor (Ph.D.) en sciences pharmaceutiques option pharmacologie Août, 2012 © Christian Jossart, 2012 Université de Montréal Faculté des études supérieures et postdoctorales Cette thèse intitulée : Le rôle et la régulation du pyroglutamylated RF-amide peptide dans le tissu adipeux lors de l’obésité Présentée par : Christian Jossart a été évaluée par un jury composé des personnes suivantes : Daniel Levesque PhD, président-rapporteur Huy Ong PhD, directeur de recherche Sylvie Marleau PhD, co-directrice Marc Servant PhD, co-directeur David St-Pierre PhD, membre du jury Hubert Vaudry PhD, examinateur externe Jean-Marc Lavoie PhD, représentant du doyen de la FES i Résumé L’obésité est définie comme un surplus de masse adipeuse. Cette condition représente un problème de santé publique devenu pandémique dans les pays industrialisés. Elle prédispose à des maladies potentiellement mortelles comme le diabète de type 2, les maladies cardiovasculaires et la stéatose hépatique non-alcoolique. L’accumulation du tissu adipeux intra-abdominal, formé d’adipocytes, est corrélée avec la résistance à l’insuline. L’augmentation de la masse adipeuse se fait par l’hyperplasie des préadipocytes, la différenciation des préadipocytes en adipocytes et l’hypertrophie des adipocytes. La différenciation des préadipocytes se fait selon l’adipogenèse qui est régulée par une multitude de facteurs, mais qui est inhibée pas les stimuli inflammatoires qui sont aussi responsables de la résistance à l’insuline et de l’apparition des problèmes de santé liés à l’obésité. Nous avons identifié un nouveau système de régulation autocrine/paracrine de l’adipogenèse dans les cellules du tissu adipeux. Le pyroglutamylated RF-amide peptide (QRFP), qui était connu pour son rôle dans la régulation de l’appétit, est un activateur de l’adipogenèse par l’activation de son récepteur, le G protein-coupled receptor 103 (GPR103). Le QRFP est exprimé dans les macrophages et les adipocytes alors que le GPR103 de sous-type b est exprimé dans les adipocytes seulement. Un traitement des adipocytes avec le QRFP augmente le captage des acides gras, l’accumulation de lipides ainsi que l’expression et l’activité de l’enzyme LPL. Le QRFP augmente aussi l’expression des gènes des transporteurs d’acides gras CD36 et FATP1, de l’enzyme activatrice d’acides gras ACSL1 et des facteurs de transcription PPAR-γ et C/EBP-α, qui sont tous impliqués dans l’adipogenèse. En plus de ses effets sur l’adipogenèse, le QRFP possède aussi un effet inhibiteur sur l’activité lipolytique induite par les catécholamines. Nous avons montré que l’expression du QRFP est diminuée dans le tissu adipeux des souris obèses. Selon nos résultats, cette diminution pourrait être expliquée par une ii augmentation des endotoxines circulantes chez les obèses, appelée endotoxémie métabolique, qui agirait, entre autres, par l’induction des interférons dans les macrophages. Les voies de signalisation de ces effets ont aussi été identifiées. Nous avons montré un autre exemple de stimulus inflammatoire qui régule les signaux adipogènes à la baisse. Mots-clés : GPR103, QRFP, obésité, adipocytes, macrophages, adipogenèse, endotoxémie métabolique, interférons, inflammation iii Abstract Obesity is defined as an excess of fat tissue mass. Obesity is a public health problem which became pandemic in developed countries. The condition of obesity predisposes to potentially fatal diseases like type 2 diabetes, cardiovascular diseases and non-alcoholic steatohepatitis. The increase in intra-abdominal adipose tissue mass is intimately associated with the development of insulin resistance. An increase in fat tissue mass occurs by preadipocytes hyperplasia, preadipocytes differentiation into adipocytes and adipocyte hypertrophy. The differentiation of preadipocytes occurs during adipogenesis and is regulated by multiple factors but inhibited by inflammatory stimuli that are responsible for insulin resistance and the emergence of obesity-related dysfunctions. We identified a new autocrine/paracrine system of regulation of adipogenesis in adipose tissue cells. The pyroglutamylated RF-amide peptide (QRFP), previously known for its role in the regulation of appetite, is an activator of adipogenesis by activating its receptor, G protein-coupled receptor 103 (GPR103). QRFP is expressed in adipocytes and macrophages whereas the GPR103 subtype b is expressed in adipocytes only. Treatment of adipocytes with QRFP increases fatty acids uptake, lipid accumulation, LPL enzyme expression and activity. QRFP upregulates gene expressions of fatty acids transporters CD36 and FATP1, of the fatty acid activating enzyme ACSL1 and of transcription factors PPAR-γ and C/EBP-α, which are all involved in adipogenesis. In addition to its effects on adipogenesis, QRFP shows an inhibitory effect on lipolytic activity induced by catecholamines. We have shown that QRFP expression is decreased in adipose tissues of obese mice. According to our results, this decrease could be explained by an increase of circulating endotoxins in obesity, called metabolic endotoxemia, which mediate its effect, in part, by the induction of interferons in macrophages. Signaling pathways of these effects have been iv identified. We demonstrated another example of inflammatory stimulus downregulating adipogenic signals. Keywords : GPR103, QRFP, obesity, adipocytes, macrophages, adipogenesis, metabolic endotoxemia, interferons, inflammation v Table des matières Résumé .................................................................................................................................... i Abstract ................................................................................................................................. iii Table des matières .................................................................................................................. v Liste des tableaux .................................................................................................................. ix Liste des figures ..................................................................................................................... x Liste des abréviations ........................................................................................................... xii Chapitre I : Introduction ......................................................................................................... 1 1. L’obésité et ses conséquences métaboliques ...................................................................... 2 1. 1. L’obésité ..................................................................................................................... 3 1. 1. 1. Les tissus adipeux et leurs implications patho-physiologiques .......................... 4 1. 1. 1. 1. Le tissu adipeux intra-abdominal (viscéral) ............................................... 5 1. 1. 1. 2. Le tissu adipeux sous-cutané ...................................................................... 7 1. 1. 1. 3. Le tissu adipeux brun ................................................................................. 7 1. 1. 2. La régulation de l’appétit ................................................................................... 8 1. 1. 2. 1. Les signaux orexigènes .............................................................................. 8 1. 1. 2. 2. Les signaux anorexigènes ........................................................................ 13 1. 1. 3. La régulation du métabolisme par l’AMPK ..................................................... 17 1. 1. 3. 1 Les modulateurs de l’activité de l’AMPK ................................................ 19 1. 1. 3. 2. Les effets périphériques de l’AMPK........................................................ 21 1. 1. 3. 3. Les effets centraux de l’AMPK ............................................................... 24 1. 1. 4. L’adipogenèse .................................................................................................. 25 1. 1. 4. 1. L’engagement ........................................................................................... 26 1. 1. 4. 2. La différenciation terminale ..................................................................... 29 1. 1. 4. 3. Les mécanismes de l’adipogenèse ........................................................... 32 1. 1. 5. La lipogenèse ................................................................................................... 36 1. 1. 6. La lipolyse ........................................................................................................ 38 1. 1. 6. 1. La régulation de la lipolyse ...................................................................... 39 vi 1. 1. 6. 2. La signalisation de la lipolyse .................................................................. 40 1. 1. 7. La thermogenèse .............................................................................................. 42 1. 1. 7. 1 Le facteur PGC-1α .................................................................................... 43 1. 1. 7. 2 La protéine UCP-1 .................................................................................... 44 1. 1. 8. Les adipokines .................................................................................................
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