L’obésité et le diabète de type 2 (DT2) sont des pathologies métaboliques associées à des perturbations de l’homéostasie glucidique et énergétique. Les enterohormones sont des acteurs importants de la regulation des mécanismes perturbés lors de ces pathologies. Parmi ces enterohormones, le GLP-1, sécrété par les cellules entéroendocrines de type L suite à un repas, permet d’amplifier la sécrétion d’insuline par les cellules β-pancréatiques et de diminuer la prise alimentaire. L’objectif de ma thèse a été de caractériser le rôle du récepteur nucléaire HNF-4γ dans l’homéostasie énergétique et la fonction endocrine de l’intestin.A l’aide d’un modèle murin d’invalidation totale et constitutive du facteur de transcription HNF-4γ, notre équipe a mis en évidence que l’absence de HNF-4γ induit une amélioration de la tolérance au glucose grâce à une augmentation du nombre de cellules L et de la quantité plasmatique de GLP-1 en réponse au glucose. L’ensemble de ces données démontre pour la première fois un rôle de HNF-4γ dans l’homéostasie glucidique via une modulation du lignage enteroendocrine spécifique du GLP-1 et suggère que son absence pourrait protéger les souris de l’établissement d’un DT2.Par ailleurs, la perte d’expression de HNF-4γ confère une protection vis-à-vis de la prise de poids et de l’intolérance au glucose normalement induites par six semaines d’un régime riche en lipides et en fructose grâce une perte énergétique accrue dans les fécès essentiellement due à une malabsorption des acides gras.En conclusion, cette étude met en exergue le rôle du récepteur nucléaire intestinal HNF-4γ dans la fonction enteroendocrine et la susceptibilité à l’obésité et au DT2. / Obesity and type 2 diabetes (T2D) are metabolic pathologies associated with glucose and energy homeostasis perturbations. Enterohormones are important players in the regulation of the mechanisms disturbed during these pathologies. Among these enterohormones, GLP-1, secreted by enteroendocrine L cells in response to a meal, potentiates insulin secretion by pancreatic β cells and inhibits food intake. The aim of my thesis was to characterize the role of the nuclear receptor HNF-4γ in the energy homeostasis and the endocrine function of the intestine.By using a total and constitutive HNF-4γ knock-out mouse model, our team has highlighted that the loss of hnf-4γ induces an improved glucose tolerance. This effect is due to an increased GLP-1 cell number and GLP-1 plasma levels in response to glucose. All together these data demonstrate for the first time a role of HNF-4γ in glucose homeostasis through a modulation of the enteroendocrine lineage specific for GLP-1 and suggest that its absence could protect mice from the T2D establishment.The loss of HNF-4γ protects mice from body weight gain and glucose intolerance normally induced by six weeks of a high-fat/high-fructose diet demonstrating its involvement in obesity and T2D. HNF-4γ -/- mice are protected from obesity by a greater energy loss in faeces mainly due to lipid malabsorption. These results demonstrate that HNF-4γ is necessary for the intestinal fatty acids uptake.In conclusion, this study highlights the role of the intestinal nuclear receptor HNF-4γ in enteroendocrine function and susceptibility to obesity and T2D.

Bile acids regulate their own synthesis through a feedback regulatory mechanism of mainly two enzymes in the classic pathway, the 7α-hydroxylase and the 12α-hydroxylase. In the early 1990's it was shown that the regulatory responses of 7α-hydroxylase are mediated at the transcriptional level and since then many positive and negative transcription factors that mediate regulatory response have been identified. An important finding was that the transcription factors regulating the expression of 7α- and 12α-hydroxylase genes are nuclear receptors.One of the first nuclear receptors identified to play a role in the transcription of the 7α-hydroxylase gene was HNF-4 since then many nuclear receptors have been identified that are involved in regulating the 7α- and 12α-hydroxylase genes. Among them the most important ones are FTF and HNF-4 which has been shown to play crucial roles in the transcription and regulation by bile acids. In this study we demonstrate the importance of FTF and HNF-4 independent of each other in the transcription and bile acid-mediated regulation of the 7α- and 12α-hydroxylase enzymes by creating promoter mutants that would either bind FTF or HNF- 4. Once the binding studies were established we performed tissue culture experiments to confirm the promoter activity and bile acid-mediated regulation with the respective promoter mutant constructs. The data from this study shows that HNF-4 is important for 7α-hydroxylase promoter activity but is not required and importantly we show that HNF-4 is not a required for the bile acid-mediated regulation of the 7α-hydroxylase. We present data which suggests that FTF is absolutely required for the promoter activity and bile acid-mediated regulation of 7α-hydroxylase. With respect to the 12α-hydroxylases how that both FTF and HNF-4 are absolutely required for promoter activity. In this study we present evidence that since the bile acid responsive elements (BARE) are similar within both the 7α- and 12α-hydroxylase promoters one can be exchanged for the other maintaining both activity and bile acid-mediated regulation.