Contributors: Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN); Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); Addenbrooke's Hospital; Cambridge University Hospitals - NHS (CUH); University of Cambridge Cambridge, UK (CAM)-University of Cambridge Cambridge, UK (CAM); Service d'Endocrinologie - Diabète - Nutrition CHRU Nancy; Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy); Institut de Génomique Fonctionnelle (IGF); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID); Institut Pasteur de Lille; Pasteur Network (Réseau International des Instituts Pasteur)-Pasteur Network (Réseau International des Instituts Pasteur)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS); Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille); Ecole Normale SupérieureEFSD/Boehringer Ingelheim European research programme (EFSD2019-20EZ13); ANR-21-CE14-0088,TriMAMvirate,Ciblage coordonné des sites de contact RE-mitochondries dans les cellules de l'intestin, du pancréas et du foie, un triumvirat pour un contrôle optimal de l'homéostasie du glucose(2021)
نبذة مختصرة : International audience ; Aims/hypothesis: Postprandial glucagon-like peptide-1 (GLP-1) secretion by enteroendocrine L cells of the gut plays an important role in glucose homeostasis, thus representing a therapeutic option of ever-growing significance for type 2 diabetes. However, the precise mechanisms linking nutrient sensing and GLP-1 secretion are incompletely understood. In this study, we focused on a potential new role for endoplasmic reticulum (ER)-mitochondria contact sites, called mitochondria-associated membranes (MAMs), in nutrient-induced GLP-1 secretion by L cells, as they are dynamically regulated by nutrients, they influence cellular calcium homeostasis crucial for hormone secretion, and their miscommunication has been implicated in alterations of glucose homeostasis in several tissues.Methods: We combined biochemical and imaging approaches to investigate nutrient-induced GLP-1 secretion, and ER-mitochondria interaction and calcium exchange in the STC-1 cell line, ex vivo ileal mouse organoids, and/or in vivo in gut enteroendocrine cells from Glu-Venus mice, both in acute conditions and after diet-induced obesity and type 2 diabetes.Results: We show here that ER-mitochondria interactions are dynamically induced by two GLP-1 secretagogues, glucose and deoxycholic acid (DCA), in STC-1 cells (1.8- and 2.1-fold, respectively), ileal mouse organoids (1.7- and 1.3-fold, respectively), and in vivo in colonic L cells of Glu-Venus mice (1.3- and 1.2-fold, respectively). In addition, glucose increased ER-mitochondria calcium exchange in STC-1 cells (1.2-fold). A paracrine action of secreted GLP-1 was also involved in the regulation of MAMs by glucose and DCA in STC-1 cells. Dynamic reinforcement of MAMs by glucose and DCA played a causal role in GLP-1 release, as both pharmacological and genetic disruption of organelle communication blocked L cell secretory response to the two stimuli in STC-1 cells. In agreement, depleting ER calcium levels or inhibiting mitochondrial calcium entry decreased glucose-induced ...
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