Molecular and cellular pathophysiologie of metabolic diseases
Équipe 6 – Université de Lille – CHU Lille – Institut Pasteur de Lille
Presentation
The “Molecular and cellular pathophysiology of metabolic diseases” team is composed of researchers, post-doctoral fellows, engineers and students. Our aim is to develop innovative strategies to elucidate through disease modelling still hidden molecular mechanisms of metabolic disorders, and, taking advantage of these basic research data, to contribute to develop innovative treatments tailored to patient’s specific cause of disease. To achieve its goals, the team 6 of RID-AGE uses integrated functional approaches from cellular and mouse models to decipher new path involved in the physiopathology of diabetes and obesity (two commonly associated diseases), and will find avenues to correct (reprogram) it.
Type 2 Diabetes (T2D) is characterized by permanent high blood glucose levels, due to inadequate pancreatic beta-cell function in the face of multi-tissue systemic insulin resistance (IR, including adipose tissue, muscle and liver). Both hyperglycemia and IR are causatively involved in T2D long-term complications, such as NASH and heart failure.
Highlights
- FRM Team Award (2021-2024) Thanks to the Fondation pour la Recherche Médicale, our team was awarded a FRM Team grant to decipher the molecular and cellular links between inflammation, beta cell dysfunctions and T2D. In this project, we aim at identifying new factors that can contribute to T2D physiopathology.
Projects
Cell cycle regulators and the metabolic control
Cell cycle regulators and the metabolic control Our research has revealed a key role for cell cycle regulators in the control of metabolic homeostasis, T2DM, obesity and hepatic steatosis by modulating the function of key metabolic tissues, such as pancreatic β cells, adipose tissue or liver (Denechaud et al., JCI, 2018 ; Giralt et al., Mol Metab 2018 ; Rabhi et al., Mol Metab, 2017; Bourouh et al., Cell Reports, 2022 ; Oger et al., BioRxiv, 2020)..
Epigenomic and epitranscriptomic regulation of metabolic homeostasis.
We are also interested in the mechanisms of cellular adaptation to metabolic stress via, in particular, the study of modifications of gene expression in connection with the environment. Our research projects are focused on defining the associated transcriptional, epigenomic and epitranscriptomic mechanisms in order to better understand their impact on the control of gene expression during metabolic adaptation. For example, we have identified the epigenomic enzyme KAT2B as a crucial regulator of insulin secretion and pancreatic β cell function during metabolic stress associated with a high fat diet (Rabhi et al., Cell Reports, 2016). We have also shown that pharmacological inhibition of histone deacetylases (HDACs) results in loss of insulin secretion associated with epigenomic and transcriptional reprogramming (Oger et al., BioRxiv, 2022). Finally, our recent data suggest that the epitranscriptome, and more specifically the m6A RNA modification and the responsible enzymes, such as FTO, is modulated by glucose and controls insulin secretion (Bornaque et al., Cells, 2022).
Transversal Projects
INS-spect
Use of mass spectrometry for the automated quantification of hormones from complex biological samples
Collaborators: Pr Benoit Deprez, INSERM U1177, Institut Pasteur de Lille; Prof. Sébastien Paul, Ecole Centrale de Lille.
This START-AIRR project funded by the Hauts de France Region Council and the ULNE I-Site had for objectives 1 / to deploy a high throughput screening method in order to identify new targets for type 2 diabetes (molecules and new genes) and 2 / to develop a method for detecting and quantifying one or more proteins of interest by mass spectrometry (multiplexing) from a complex biological sample. Our promising results have enabled us to identify new molecules whose efficacy and mode of action will be studied further in our laboratories.
Micro3DBETA
Developing a 3D dynamic microfluidic device of pancreatic beta cells and adipocytes to modelize multi-organ cross-talks during type 2 diabetes development
Collaborator : Dr Anthony Treizebre, IEMN, Lille.
The development of alternative approaches to animal testing is also strengthened by the 3Rs rule (Replace, Reduce, Refine) of the European commission (Directive 2010/63/EU) governing animal use. In the PhD project entitled “Developing a 3D dynamic microfluidic device of pancreatic beta cells and adipocytes to modelize multi-organ cross-talks during type 2 diabetes development” (Micro3DBeta), we will go beyond these challenges by developing multi-disciplinary and intersectoral approaches to implement microfluidic platforms dedicated to the specific analysis of the organ cross-talk in the context of T2D. This research project will be co-supervised by experts in T2D research, micro/nanotechnologies and organoid development. These studies will be conducted in the Research Unit CNRS UMR8199 at the European Genomic Institute for Diabetes, in the Institut d’Electronique, de Microélectronique et de Nanotechnologies (IEMN), and in close collaboration with our private partner HCS Pharma.
MIMESIS
Role of the E2F1 pathway in the loss of function of pancreatic β cells linked to inflammation during aging.
Collaborator: Dr Benoit Pourcet, Dr Joel Haas, INSERM U 1011, Institut Pasteur de Lille)
Type 2 diabetes is characterized by high blood sugar and develops due to the insufficient ability of pancreatic beta cells to produce insulin. The incidence and susceptibility to type 2 diabetes increases with age, but the underlying mechanism(s) in beta cells that contribute to this increased susceptibility have not been fully understood. We propose in the MELODIE project to study the role of inflammation in the loss of function of pancreatic beta cells during aging. We thus hope, through this project, to identify new targets responsible for the premature aging of insulin-producing cells in order to develop original therapeutic strategies that will constitute the treatments of tomorrow.
Members
CRCN Inserm, responsable de groupe
Numéro ORCID : 0000-0002-2109-4849
Post-doc, INSERM
Assistante ingénieure, IPL
Étudiant en thèse, Univ Lille, Inserm, I-Site
Etudiante en M2R
Publications
Bourouh C, Courty E, Rolland L, Pasquetti G, Gromada X, Rabhi N, Carney C, Moreno M, Boutry R, Caron E, Benfodda Z, Meffre P, Kerr-Conte J, Pattou F, Froguel P, Bonnefond A, Oger F, Annicotte JS.
The transcription factor E2F1 controls the GLP-1 receptor pathway in pancreatic cells..
Cell Reports. 2022 Aug 9;40(6):111170. doi: 10.1016/j.celrep.2022.111170. PMID: 35947949
Paiva I, Cellai L, Meriaux C, Poncelet L, Nebie O, Saliou JM, Lacoste AS, Papegaey A, Drobecq H, Le Gras S, Schneider M, Malik EM, Müller CE, Faivre E, Carvalho K, Gomez-Murcia V, Vieau D, Thiroux B, Eddarkaoui S, Lebouvier T, Schueller E, Tzeplaeff L, Grgurina I, Seguin J, Stauber J, Lopes LV, Buée L, Buée-Scherrer V, Cunha RA, Ait-Belkacem R, Sergeant N*, Annicotte JS*, Boutillier AL*, Blum D*.
Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription. Journal of Clinical Investigation.
2022 Jun 15;132(12):e149371. doi: 10.1172/JCI149371. PMID: 35536645; PMCID: PMC9197525.
Bornaque F, Delannoy CP, Courty E, Rabhi N, Carney C, Rolland L, Moreno M, Gromada X, Bourouh C, Petit P, Durand E, Pattou F, Kerr-Conte J, Froguel P, Bonnefond A, Oger F, Annicotte JS*.
Glucose Regulates m6A Methylation of RNA in Pancreatic Islets.
Cells. 2022 Jan 15;11(2):291. doi:10.3390/cells11020291. PMID: 35053407; PMCID: PMC8773766
de Toledo M, Lopez-Mejia IC, Cavelier P, Pratlong M, Barrachina C, Gromada X, Annicotte JS*, Tazi J*, Chavey C*.
Lamin C Counteracts Glucose Intolerance in Aging, Obesity, and Diabetes Through β-Cell Adaptation.
Diabetes. 2020 Apr;69(4):647-660. doi: 10.2337/db19-0377. Epub 2020 Jan 31. PMID: 32005707
Rabhi N, Hannou SA, Gromada X, Salas E, Yao X, Oger F, Carney C, Lopez-Mejia IC, Durand E, Rabearivelo I, Bonnefond A, Caron E, Fajas L, Dani C, Froguel P, Annicotte JS
Cdkn2a deficiency promotes adipose tissue browning.
Mol Metab. 2018 Feb;8:65-76. doi: 10.1016/j.molmet.2017.11.012. Epub 2017 Dec 1. PMID: 29237539; PMCID: PMC5985036
Rabhi N, Denechaud PD, Gromada X, Hannou SA, Zhang H, Rashid T, Salas E, Durand E, Sand O, Bonnefond A, Yengo L, Chavey C, Bonner C, Kerr-Conte J, Abderrahmani A, Auwerx J, Fajas L, Froguel P, Annicotte JS.
KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response
Cell Rep. 2016 May 3;15(5):1051-1061. doi: 10.1016/j.celrep.2016.03.079. Epub 2016 Apr 21. PMID: 27117420.