Premature ovarian Insufficiency (POI) is the cessation of the ovarian function before the age of 40, defined by high serum gonadotrophins, low estradiol and amenorrhea for at least 4 months. The etiology may be iatrogenic after a surgery, chemotherapy or radiotherapy treatment, environmental, autoimmune or genetic. However, in most of the cases the cause remains unknown. Clinical and family studies suggest a strong heritability of age at menopause and POI, but the number of genetic causes and genes identified to be involved in human POI remains very small. In POI patients, the two crucial functions of the ovary, hormonal secretion and reproduction, are absent. In the last decades, however, new advances in assisted reproduction techniques have allowed the possibility of carrying pregnancies to POI women, thanks to oocyte donation. The aim of this study was to identify new genetic factors implicated in the development of POI women and to analyse the reproductive possibilities and outcome of women with a genetic cause of POI. For the first part of the study, the DNA of a cohort of POI women recruited in the Fertility Clinic of the Hôpital Erasme of the Université Libre de Bruxelles was used to sequence five candidate genes (FSHR, GDF9, BMP15, AMH and AMHR2) known to be implicated in the ovarian folliculogenesis. The most important findings were two very rare variants and one unknown variant in the AMH gene. The functional study performed with these variants suggested a diminished function of the mutant protein. Furthermore, one of the variants was found in the mother of one of the patients, who was also diagnosed of POI at 32 years old. These arguments strongly suggest that a defective AMH could play a role in the development of POI. This is supported by previous studies with knock out mice models, which show an earlier depletion of the ovarian follicle pool due to a faster recruitment of the primordial follicles that constitute the ovarian reserve. The sequencing of the BMP15 gene led to the identification of two new variants not identified among controls but not predicted to be deleterious. Interestingly, one variant previously reported in POI women and predicted to be deleterious for the protein function, was found in a Sub-Saharan African POI patient as well as in our control cohort. This variant was already studied functionally and shown to have a reduced biological activity. However, we identified this variant in 6% of the Sub-Saharan African control population, which suggests that this is a more prevalent variant in the African genotype and raises up the importance of the ethnicity when studying genetic variants.The sequencing of the other genes (FSHR, GDF9 and AMHR2) did not lead to any association with POI.In the second part of the study, 24 women with Turner syndrome and POI were analysed in terms of reproductive, obstetrical and perinatal outcome after oocyte donation. This specific group of patients was chosen because of their specific systemic anomalies that could interfere with pregnancy outcome and because very few reports have been published on this subject. In the 23 patients finally transferred, the pregnancy rate was similar to that obtained after oocyte donation in other cohorts. There was a miscarriage rate of 23% and a rate of complications of pregnancy as high as 50%, mainly caused by pregnancy-induced hypertensive diseases. Four women at risk of genetic POI were included in the fertility preservation program in order to vitrify their oocytes. Three of them have already vitrified successfully their oocytes but none of them has yet used them.Oocyte vitrification represents a new hope for those women with genetic risk of POI to be able to carry a pregnancy with their own oocytes.In conclusion, three variants of the AMH gene could be implicated in the development of POI as demonstrated by the reduced in vitro bioactivity of the variants and the familial segregation of the cases. Since then, it sounds plausible to propose AMH sequencing in the case of familial POI and secondary amenorrhea.In the BMP15 gene, 2 new variants were predicted to be tolerated. A potentially deleterious variant of the BMP15 gene (L148P) previously associated to POI, was also found in 6% of the Sub-Saharan African controls which suggests that it is a common variant in the African ethnic. No clear association was found between the other tested candidate genes and our POI cohort.Regarding Turner’s Syndrome pregnancies, we can conclude that they are high-risk pregnancies that need of a multidisciplinary follow-up before and during pregnancy.Oocyte cryopreservation represents a new tool to be offered to women at risk of genetic POI to preserve their fertility, but not without previous genetic counselling. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

The prevalence of type 2 diabetes is increasing dramatically worldwide. Type 2 diabetes is a major health and socio-economic burden. Genetic predisposition and the obesity epidemic, due to sedentary life style and high caloric food intake, are associated with development of type 2 diabetes. Circulating free fatty acids (FFAs), in particular saturated FFAs, are linked with insulin resistance and β cell dysfunction. Following this background we performed RNA sequencing of human pancreatic islets treated with the saturated FFA palmitate to acquire a global image of the islet response to this insult. We identified several stress pathways induced by palmitate with a major induction of the endoplasmic reticulum (ER) stress response. The ER stress response, in particular the PKR-like ER kinase (PERK) branch, has been shown to be induced by saturated FFA. It leads to increased β cell apoptosis both in fluorescence activated cell sorter (FACS) purified rat β cells and human islets. We further clarified the role of this pathway by studying the involvement of the constitutive repressor of eIF2α phosphorylation (CReP) in a monogenic form of diabetes. CReP is a repressor of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation. A direct target of PERK, eIF2α is involved in translational attenuation and induction of apoptosis. We have shown that CReP loss-of-function leads to a new syndrome of young onset diabetes, intellectual disability and microcephaly. The identified R658C mutation abrogated CReP activity leading to increased eIF2α phosphorylation and β cell apoptosis. To further demonstrate the importance of eIF2α dysregulation in β cell demise, we used guanabenz, a chemical inhibitor of growth arrest DNA damage inducible 34 (GADD34). GADD34 is an ER stress-induced repressor of eIF2α phosphorylation. Guanabenz potentiated FFA-mediated ER stress and apoptosis in clonal and primary rat β cells and in human islets through the activation of CCAAT/enhancer binding protein homologous protein (CHOP), downstream of eIF2α. Guanabenz administration in mice impaired glucose tolerance and led to β cell dysfunction. In ex vivo experiments guanabenz also induced β cell dysfunction in mouse and rat islets.In conclusion our data demonstrate that the dysregulation of signaling in the PERK/eIF2α pathway is crucial for β cell demise. Together with previously reported monogenic diabetes caused by loss-of-function mutations in PERK in man and the eIF2αS51A mutation in mice, our findings suggest that a narrow regulation of PERK/eIF2α signaling is central for proper β cell function and survival. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

Les altérations du cycle veille/sommeil sont fréquentes dans le milieu militaire. Elles induisent une dégradation des performances, et peuvent potentiellement causer des conséquences sur l’état de santé à long terme des personnels. Ce travail de thèse a pour objectif d’évaluer deux contre-mesures, l’effet de 6 nuits d’extension de sommeil d’une part et les effets de 8 semaines d’entrainement physique d’autre part sur la performance cognitive (attention soutenue, inhibition, mémoire de travail), la pression de sommeil, les réponses endocriniennes et inflammatoires, et la fonction neuromusculaire au cours d’une privation totale de sommeil et de la récupération subséquente. Les résultats principaux mettent en évidence que six nuits d’extension de sommeil ont pour effet de limiter (i) la dégradation de la performance cognitive (attention soutenue et mémoire de travail) et physique, (ii) l’apparition de micro-sommeils observées au cours d’une période de privation totale de sommeil. L’extension de sommeil a également induit une diminution des concentrations circulantes de prolactine et une augmentation des concentrations circulantes d’IGF-1. Les résultats ont également montré que 8 semaines d’entrainement physique permettent de limiter la dégradation de la performance psychomotrice (i.e. conduite simulée) induite par la privation totale de sommeil sans modifications significatives des réponses endocriniennes. Ainsi, ces types de stratégies préventives permettraient de limiter les dégradations de la performance et pourraient être combinées à des contre-mesures nutritionnelles et/ou pharmacologiques / The alterations of sleep/wake cycle are frequent in military area. They induce performance degradation and can potentially induced some consequences on health status in the long-term among military personnel. The aim of this thesis work is to assess two countermeasures, the effects of six nights of sleep extension and the effects of 8 weeks of physical training on cognitive performance (sustained attention, inhibition, working memory), sleep pressure, hormonal and inflammatory responses and neuromuscular function during total sleep deprivation and the subsequent period. The main results are that 6 nights of sleep extension limit (i) degradation of cognitive performance (sustained attention and working memory) and physical performance, (ii) involuntary micro-sleeps during total sleep deprivation period. Likewise, the sleep extension induces a decrease of circulating prolactin concentration and an increase of circulating IGF-1 concentration. Results have shown that 8 weeks of physical training limit the degradation of psychomotor performance (i.e. simulated driving) induced by total sleep deprivation without changes in hormonal responses. Thus these kinds of preventives strategies would limit the performance degradation and could be combined with nutritional and/or pharmacological countermeasures

Pregnancy is a condition leading to an important strain on thyroid morphology and function.A normal functioning of the thyroid gland in the mother is essential for the early fetal development, since the fetal thyroid does not produce thyroid hormones until the end of the first trimester (approximately 12 to 14 weeks).The impact of thyroid dysfunction (and especially hypothyroidism) during pregnancy is well documented and has been associated with a number of obstetrical complications, such as premature delivery, low birth weight and even fetal death. In view of all changes in thyroid physiology during pregnancy the ATA (American Thyroid Association) guidelines recommend using trimester- and population-specific normality ranges, to define thyroid dysfunction. It is proposed to determine them in pregnant women without thyroid antibodies (TPO) and without severe iodine deficiency. Due to the few numbers of randomized clinical trials, there is still no consensus whether all pregnant women should be screened or only women at risk for the development of thyroid dysfunction during pregnancy.Thyroid dysfunction during pregnancy is caused in most cases by the presence of thyroid autoimmunity (TAI) and also the altered pregnancy outcomes in most studies are associated with the presence of TAI.Besides the presence of TAI, other factors might also change, influence and/or modify thyroid function. When we started our research, there were only few studies that investigated the impact of other variables, such as iron, BMI, smoking habit and/or the background of the pregnant women on the prevalence of thyroid dysfunction during the first trimester of pregnancy.The aims of the thesis were therefore, to investigate: • the association between the iron reserve status (ferritin levels), thyroid (dys)function and autoimmunity, corrected for confounders such as age, BMI, smoking habit and the time of blood sampling;• the impact of the ethnic background of the pregnant woman on thyroid function and autoimmunity, corrected for confounders such as age, BMI, smoking habit, and the time of blood sampling. Furthermore, to determine ethnic-specific reference ranges and investigate their impact on the diagnosis of thyroid dysfunction;• the impact of changes in thyroid function within the normal reference range in women free of thyroid autoimmunity on pregnancy outcomes, corrected for established covariates (age, BMI, smoking) and iron reserve as candidate new variable.• whether targeted high-risk screening for thyroid dysfunction during pregnancy could be improved with the inclusion of iron status and ethnicity to the actual risk factors defined in the ATA-GL.The results can be summarized as follows:Thyroid function during pregnancy can be influenced by variables others than thyroid antibodies such as the iron status and the ethnical background of the women. However, their impact on thyroid function is less important compared to that of thyroid antibodies. No significant impact of well-known variables (BMI, age, smoking) and others such as iron has been shown on clinical pregnancy outcomes when thyroid function remained within the normal range and no thyroid antibodies were present.We have shown that adding variables such as iron deficiency, ethnic background and obesity to the currently provided list of factors leading to a high-risk for the development of thyroid dysfunction during pregnancy, might improve the detection rate of subclinical hypothyroidism to comparable rates obtained in case of universal screening. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

L'utilisation de la biologie moléculaire pour la caractérisation des enzymes impliquées dans le métabolisme des hormones stéroïdiennes a fait progresser de manière importante les connaissances en endocrinologie. L'étude de la stéroïdogenèse a mené à d'importantes découvertes, notamment en ce qui a trait au traitement du cancer de la prostate et à diverses avenues thérapeutiques pour lutter contre le cancer du sein. Récemment, notre laboratoire a décrit la 17P-HSD de type 12, une enzyme impliquée dans la formation de l'estradiol chez l'humain. Ce mémoire poursuit les analyses amorcées en caractérisant l'orthologue murin de cette enzyme tout en identifiant un ancêtre commun chez C. elegans. La faible taille de la chaîne latérale de l'acide aminé en position 234 (alanine et méthionine) chez ces deux homologues comparativement à l'enzyme humaine (phénylalanine) permet l'entrée de substrats plus gros au site actif, ce qui affecte la spécificité. Je démontrerai donc que la 17P-HSD de type 12 chez la souris et chez C. elegans catalyse aussi bien la formation des androgènes que des estrogènes. / The use of molecular biology in the characterisation of enzymes involved in steroid hormone biosynthesis has led to great advances in endocrinology. Prostate cancer treatment and breast cancer therapies are some examples of tremendous discoveries which took place due to our understanding of steroidogenesis. Recently, our research group described type 12 17P-HSD which activates estrone by transforming it into estradiol, a powerful estrogen in human. This thesis focuses on the characterisation of its mouse and C. elegans homologs. The smaller size of amino acid 234 permits the entry of a wider variety of substrates into the active site of those two homologs compared to the human enzyme, thus affecting the specificity. In this work, I will prove that mouse and C. elegans type 12 17PHSD catalyzes the formation of both androgens and estrogens

Dans cette étude, nous nous sommes principalement intéressés aux changements transcriptionnels des cellules de la granulosa (CG) durant la période pré-ovulatoire afin de mieux caractériser le rôle du pic de LH avant l'ovulation. Nous avons trouvé qu'avant le pic de LH, les CG exercent principalement des fonctions de division et de prolifération cellulaire, après le pic de LH, les CG sont impliquées dans la vascularisation et la synthèse de lipides, tandis que la réponse plus tardive suite au pic de LH, montrent des fonctions de localisation et de transport protéique. Ensuite, dans une optique plus appliquée à l'industrie bovine, nous avons investigué la présence de marqueurs moléculaires dans les CG associés à la compétence au développement embryonnaire de 1'ovocyte. Nous avons identifiés 18 transcrits sur-exprimés dans les CG associés aux ovocytes compétents. Plusieurs de ces marqueurs sont associés à la chromatine, au cycle cellulaire et à la stabilité de l'ADN. De plus, parmi les marqueurs trouvés, certaines séquences, malgré leur alignement sur le génome bovin, ne correspondent à aucun gène connu. Deux de ces nouvelles régions transcrites (NTR) se retrouvent près du gène de l'INHBA et pourraient constituer soit un variant d'épissage, soit un élément de régulation en 3'UTR. Les différents marqueurs trouvés dans les CG constituent un moyen non-invasif qui permettra de discriminer quels ovocytes ont le plus de potentiel à former un embryon sans que le gamète lui-même soit utilisé. Finalement, puisqu'il existe sur le marché plusieurs méthodes pour effectuer l'hybridation des biopuces, les cinq principales étapes de la préparation des échantillons et la validation post-hybridation par qRT-PCR ont été évalués. Dans l'ensemble, ces études ont permis de mettre en lumière les différentes étapes transcriptionnelles que les CG doivent compléter avant l'ovulation ainsi que quelques transcrits associés au statut de compétence de 1'ovocyte. Ultimement, une meilleure connaissance de la signature transcriptionnelle des CG à différentes étapes de la folliculogenèse permettra d'améliorer la stimulation ovarienne et la production embryonnaire subséquente.

Dans un contexte mondial d’émergence de bactéries résistantes aux antibiotiques, il est nécessaire d’explorer de nouvelles voies de recherche pour trouver de nouveaux traitements. Cet état de fait est particulièrement marqué dans le cadre d’infections chroniques associées à une colonisation des tissus par des biofilms bactériens. L’endocrinologie microbienne est un champ de recherche axé sur l’étude des mécanismes de communication inter-règnes qui peut s’établir entre des bactéries et leurs hôtes. Les molécules humaines qui permettent ce dialogue constituent de potentiels outils capables de moduler la physiologie des bactéries pour empêcher leur développement. Dans cette optique, l’objectif de ma thèse était d’approfondir nosconnaissances sur l’effet des peptides natriurétiques, une famille d’hormones humaines, sur la physiologie du pathogène opportuniste P. aeruginosa. Les travaux que j’ai menés ont permis de préciser les mécanismes de l’action anti-biofilm du peptide natriurétique de type C ou CNP. J’ai également montré qu’un autre peptide, le peptide natriurétique atrial (ANP), est capable de disperser un biofilm établis de P. aeruginosa. Dans un second temps, j’ai pu identifier que l’opéron ami, dans son intégralité, est indispensable aux effets des peptides natriurétiques et qu’en plus les protéines codées par les gènes de l’opéron ami ont un rôle important dans la régulation de la virulence bactérienne et dans la formation des biofilms. Ainsi, j’ai pu mettre en évidence que les protéines AmiE et AmiR, en plus de leur rôle dans le métabolisme secondaire, sont impliquées dans la régulation de la virulence et de la formation de biofilm de P. aeruginosa. / In a global context of emergence of antibiotic-resistant bacteria, it is necessary to explore new paths of research to find new treatments. This state of affairs is particularly marked in the context of chronic infections associated with tissue colonization by bacterial biofilms. Microbial endocrinology is a field of research focused on the study of inter-kingdom communication that can be established between bacteria and their hosts. The human molecules that allow this dialogue are potential tools capable of modulating bacterial physiology to prevent their development. In this perspective, the aim of my thesis was to deepen our knowledge about the effect of natriuretic peptides, a family of human hormones, on the physiology of the opportunistic pathogen P. aeruginosa. The work that I carried out allowed us to characterize the mechanisms of the anti-biofilm action of the natriuretic peptide type C or CNP. I have also shown that another peptide, the atrial natriuretic peptide (ANP), is able to disperse an established biofilm of P. aeruginosa. In a second step, I was able to identify that the entire ami operon is essential for the effects of the natriuretic peptides and that the proteins encoded by the genes of the ami operon have an important role in bacterial virulence regulation and in the formation of biofilms. Thus, I was able to demonstrate that the AmiE and AmiR proteins, in addition to their role in secondary metabolism, are involved in the regulation of virulence and biofilm formation of P. aeruginosa.

La maladie de Cushing résulte du développement de tumeurs hypophysaires corticotropes d’agressivité variable. Cette forme d'hypercorticisme dépendante de l’ACTH se distingue des formes indépendantes de l’ACTH, souvent consécutives à une tumeur surrénalienne. Les outils de distinction entre ces deux formes ainsi que les marqueurs d’agressivité des tumeurs hypophysaires ont été peu documentés ; ils seraient pourtant précieux pour les cliniciens. Un premier objectif, atteint, de notre travail a visé à identifier sur des cohortes cliniquement caractérisées de chiens atteints de syndrome de Cushing, des marqueurs sanguins et morphologiques qui soient distinctifs des deux formes de syndromes de Cushing (concentration plasmatique en ACTH, échographie et examen tomodensitométrique des glandes surrénales). Un second objectif de notre travail a visé à identifier des paramètres cliniques et biologiques susceptibles de refléter l'agressivité des tumeurs corticotropes. Nous avons ainsi montré chez le chien qu'une hypothermie ou une bradycardie peut signer une tumeur de grande taille. Chez le chat, atteint d'adénomes corticotropes généralement agressifs, nous avons démontré que le dosage de la POMC plasmatique est pertinent pour diagnostiquer la maladie de Cushing. La valeur élevée de la concentration plasmatique en POMC chez l'homme, le chien et le chat, a suggéré que ces tumeurs induisent un défaut de maturation de la POMC. L'analyse par western-blot des acteurs protéiques de cette maturation chez le chien a en effet révélé une diminution de la quantité d'enzyme pro-convertase 1/3 au sein des tumeurs corticotropes de grande taille. / Cushing’s disease or hyperadrenocorticism (HAC) is one of the most frequent endocrine diseases in dogs. Most cases are ACTH-dependent HAC and are associated with pituitary tumors of variable aggressiveness. The other form of HAC is known as ACTH-independent. The present work was carried out on cohort of dogs and cats presented with HAC. The first objective of this work was to assess the accuracy of diagnostic investigations (such as adrenal glands ultrasonography, computed tomodensitometry scan of adrenal glands and pituitary gland and basal ACTH measurement) in a large cohort of dogs with HAC and to identify the best thresholds that allow a correct classification of HAC (ACTH dependent vs ACTH independent). The second objective was to demonstrate that clinical information such as bradycardia or hypothermia reflect the aggressiveness of the pituitary tumor. We also demonstrated that plasma proopiomelanocortin (POMC) concentration was elevated in cats with Cushing’s disease. This observation, previously reported in dogs and humans, suggests a physiopathological implication of ACTH loss of maturation in aggressive pituitary tumour. We investigated if proconvertase 1/3 (PC1/3) could be involved in this alteration through western blot detection of POMC, pro-ACTH, ACTH and PC1/3 in corticotropic tumors. This work showed a difference in PC1/3 protein levels between large and small corticotroph tumours, PC1/3 signal being weak to undetectable in large pituitary tumours.

Les GEPNETs (tumeurs neuroendocrines gastroentéropancréatiques), représentent le deuxième cancer digestif. L’octréotide (agoniste Sst2) contrôle efficacement leurs sécrétions et plus modérément la croissance cellulaire. Au cours de ma première partie de thèse, j’ai développé la culture primaire de GEPNETs humaines. Ceci m’a permis d’étudier l’effet antiprolifératif et antisécretoire du pasireotide (pan agoniste Sst) et de l’évérolimus (inhibiteur de la voie pi3 kinase Akt) en comparaison avec l’octréotide. J’ai mis en évidence un effet inhibiteur significatif et similaire de l’octréotide et du pasiréotide sur la viabilité cellulaire et la sécrétion de chromogranine A. Cependant, le trafic intracellulaire du Sst2 est diffèrent en présence de pasireotide. L’évérolimus inhibe la viabilité et la secretion cellulaire des GEPNETs de manière similaire aux SSA. Nous n’avons pas retrouvé d’additivité entre l’évérolimus et les SSA. Dans la deuxième partie de mon travail j'ai étudié l’effet de la surexpression du Sst2 dans les cellules de prolactinomes et NFPA humains. Apres surexpression de Sst2, l’octréotide est capable d’inhiber la sécrétion de PRL et la prolifération cellulaire des NFPAs. Cette surexpression n’améliore pas la sensibilité aux dopastatines (agonistes chimériques Sst2-D2DR) des prolactinomes alors qu’une amélioration est bien observée dans les NFPAs. En conclusion, la culture primaire des GEPNETs représente un bon modèle d’étude pharmacologique. La coopération Sst2–D2DR dans les NFPA est effective dans ce modèle et permettra l’étude des mécanismes mises en jeu par les dopastatines. / GEPNETs represent, in terms of prevalence, the second digestive cancer. Octreotide (Sst2 agonists) effectively control their secretion and partially cell growth. we developed a primary cell culture of human GEPNETs. Cell culture allowed the study of antisecretory and antiproliferative effect of pasireotide and everolimus, alone or in combination, as compared to octreotide, in 20 tumors. We highlighted a significant and similar maximal inhibitory effect of octreotide and Pasireotide either on cell viability or on chromogranin A secretion in all analyzed tumors. However, the intracellular trafficking of Sst2 was strikely different in the presence of pasireotide and octreotide. In all analyzed tumors, everolimus inhibits cell viability and secretion of GEPNETs similarly to SSA. We couldn’t reveal any additivity between everolimus and SSA in cell viability suppression.My second goal was to study the effect of overexpression of Sst2 by adenoviral transfer in cells of human prolactinomas and NFPA. In both cell types. Nevertheless, octreotide efficiently suppressed PRL secretion and cell proliferation (NFPA). Overexpression of Sst2 did not improve the efficcacy of dopastatines (chimeric Sst2 - D2DR agonists) on prolactin secretion in prolactinomas, but clealy improved suppression of cell proliferation in NFPA. These results suggest that dopostatin promotes a Sst2 D2DR cooperation in NFPA, but not in prolactinomas, where DRDR activation remains dominant. In conclusion, GEPNETs primary cell culture represents a good model for pharmacological In pituitary adenomas, Sst2 overexpression opens an interesting perspective for gene therapy in recurrent NFPA after surgery.

La leptine est une hormone adipocytaire impliquée notamment dans le contrôle de la balance énergétique et de la sécrétion d'hormone de croissance (GH). Ses récepteurs ObRa et ObRb sont exprimés dans les cellules somatotropes de rat, et elle régule l'expression hypophysaire du récepteur de la ghréline. Dans notre modèle de rats obèses DIO, l'altération des taux plasmatiques de GH caractéristique de cette pathologie n'est pas liée à la résistance hypophysaire à la leptine. Chez les rats Lou/C, la GH participe à la résistance à l'obésité, les hormones ghréline et leptine jouant un rôle prépondérant dans le contrôle hypophysaire de sa sécrétion. In vitro, l'internalisation de ObRb est constitutive mais la leptine inhibe l'adressage de ce récepteur de l'appareil de Golgi vers la membrane plasmique. Cette internalisation est indispensable pour l'activation de STAT3 et ce processus pourrait donc participer à l'établissement de la résistance à la leptine.