Patricia Serradas1, Agnès Ribeiro2, Céline Osinski3, Léa Le Gléau3, Christine Poitou3,4, Juan de Toro-Martin5,6, Laurent Genser3,7, Magali Fradet8,9, Hédi Antoine Soula3, Armelle Leturque3, Corinne Blugeon10, Laurent Jourdren10, Edwige Ludiwyne Hubert5,11, Karine Clément3,4. 1. Sorbonne Université, INSERM, Nutrition and obesities: systemic approaches, F-75013, Paris, France. patricia.serradas_pacheco@sorbonne-universite.fr. 2. Sorbonne Université, INSERM, Nutrition and obesities: systemic approaches, F-75013, Paris, France. agnes.ribeiro@sorbonne-universite.fr. 3. Sorbonne Université, INSERM, Nutrition and obesities: systemic approaches, F-75013, Paris, France. 4. Nutrition Department, Pitié-Salpêtrière hospital, Assistance Publique/Hôpitaux de Paris, F-75013, Paris, France. 5. Sorbonne Université, Université de Paris, INSERM, Cordeliers Research Center, F-75006, Paris, France. 6. Institute of Nutrition and Functional Foods (INAF), School of Nutrition, Université Laval, Quebec, QC, Canada. 7. Hepato-Biliary-Pancreatic Gastrointestinal Surgery and Liver Transplantation, Pitié-Salpêtrière Hospital, Assistance Publique/Hôpitaux de Paris, F-75013, Paris, France. 8. Cytometry platform, Institut Cardiometabolism and Nutrition, F-75013, Paris, France. 9. Institut de Biologie, CIRB, Collège de France, F-75005, Paris, France. 10. Genomics core facility, Département de biologie, Institut de Biologie de l'ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005, Paris, France. 11. SERVIER, ADIR, F-92284, Suresnes, cedex, France.
Abstract
OBJECTIVES: Altered enteroendocrine cell (EEC) function in obesity and type 2 diabetes is not fully understood. Understanding the transcriptional program that controls EEC differentiation is important because some EEC types harbor significant therapeutic potential for type 2 diabetes. METHODS: EEC isolation from jejunum of obese individuals with (ObD) or without (Ob) type 2 diabetes was obtained with a new method of cell sorting. EEC transcriptional profiles were established by RNA-sequencing in a first group of 14 Ob and 13 ObD individuals. EEC lineage and densities were studied in the jejunum of a second independent group of 37 Ob, 21 ObD and 22 non obese (NOb) individuals. RESULTS: The RNA seq analysis revealed a distinctive transcriptomic signature and a decreased differentiation program in isolated EEC from ObD compared to Ob individuals. In the second independent group of ObD, Ob and NOb individuals a decreased GLP-1 cell lineage and GLP-1 maturation from proglucagon, were observed in ObD compared to Ob individuals. Furthermore, jejunal density of GLP-1-positive cells was significantly reduced in ObD compared to Ob individuals. CONCLUSIONS: These results highlight that the transcriptomic signature of EEC discriminate obese subjects according to their diabetic status. Furthermore, type 2 diabetes is associated with reduced GLP-1 cell differentiation and proglucagon maturation leading to low GLP-1-cell density in human obesity. These mechanisms could account for the decrease plasma GLP-1 observed in metabolic diseases.
OBJECTIVES: Altered enteroendocrine cell (EEC) function in obesity and type 2 diabetes is not fully understood. Understanding the transcriptional program that controls EEC differentiation is important because some EEC types harbor significant therapeutic potential for type 2 diabetes. METHODS: EEC isolation from jejunum of obese individuals with (ObD) or without (Ob) type 2 diabetes was obtained with a new method of cell sorting. EEC transcriptional profiles were established by RNA-sequencing in a first group of 14 Ob and 13 ObD individuals. EEC lineage and densities were studied in the jejunum of a second independent group of 37 Ob, 21 ObD and 22 non obese (NOb) individuals. RESULTS: The RNA seq analysis revealed a distinctive transcriptomic signature and a decreased differentiation program in isolated EEC from ObD compared to Ob individuals. In the second independent group of ObD, Ob and NOb individuals a decreased GLP-1 cell lineage and GLP-1 maturation from proglucagon, were observed in ObD compared to Ob individuals. Furthermore, jejunal density of GLP-1-positive cells was significantly reduced in ObD compared to Ob individuals. CONCLUSIONS: These results highlight that the transcriptomic signature of EEC discriminate obese subjects according to their diabetic status. Furthermore, type 2 diabetes is associated with reduced GLP-1 cell differentiation and proglucagon maturation leading to low GLP-1-cell density in human obesity. These mechanisms could account for the decrease plasma GLP-1 observed in metabolic diseases.
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