Molecular and cellular pathophysiology of metabolic diseases

Team 2 – CNRS UMR 1283/8199 – Lille University – CHU Lille – Institut Pasteur de Lille

Presentation

Highlights

• 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).

• Epigenomic 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).

• MetaboMIR. We have also obtained an industrial chair with the biotechnology company AptamiR (“metaboMIR”, 2020-2023), funded by the European Metropole of Lille and the I-Site ULNE. The general objective of MetaboMIR is to identify and validate new therapeutic targets and their modes of action in order to generate, in the long term, new treatments to fight against certain metabolic diseases in humans, including diabetes, obesity and “NAFLD / NASH” non-alcoholic fatty liver disease. This industrial chair also aims to promote training in and through research, teaching and the transmission of our scientific expertise in the Lille ecosystem.

Transversal projects

KABETE/Beta 

Identification of new molecules modulating insulin secretion and glucose metabolism.
Collaborator : Pr Benoit Deprez, INSERM U1177, Institut Pasteur de Lille.
These two maturation projects (funded by SATT Nord) aimed to identify new and original small molecules for the treatment of T2DM and to identify the mode of action of these molecules.

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 aims 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 in our laboratories within EGID.

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.

MELODIE

Role of the E2F1 pathway in the loss of function of pancreatic β cells linked to inflammation during aging.
Collaborator : Dr Benoit Pourcet, INSERM U 1011, Institut Pasteur de Lille).
T2D 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 T2D 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

Marie-Jennifer BARAKA-VIDOT
Post-doc, CNRS

Charlène CARNEY
Engineer assistant, Inserm

Florine BORNAQUE
PhD student, Univ Lille

Leonid PLINER
PhD student, Univ Lille, Inserm, I-Site

Publications

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. * co-last author.

López-Cayuqueo KI, Chavez-Canales M, Pillot A, Houillier P, Jayat M, Baraka-Vidot J, Trepiccione F, Baudrie V, Büsst C, Soukaseum C, Kumai Y, Jeunemaître X, Hadchouel J, Eladari D, Chambrey R.
A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of renal tubular acidosis.
Kidney Int. 2018 Sep;94(3):514-523. doi: 10.1016/j.kint.2018.05.001. Epub 2018 Jul 7. PMID:30146013.

Lecoutre S, Oger F, Pourpe C, Butruille L, Marousez L, Dickes-Coopman A, Laborie C, Guinez C, Lesage J, Vieau D, Junien C, Eberlé D, Gabory A, Eeckhoute J, Breton C.
Maternal obesity programs increased leptin gene expression in rat male offspring via epigenetic modifications in a depot-specific manner.
Mol Metab. 2017 May 31;6(8):922-930. doi: 10.1016/j.molmet.2017.05.010. PMID: 28752055; PMCID: PMC5518658.

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.

Keywords

Type 2 diabetes ; Physiology ; Pathophysiology ; Kidney diseases ; Adipose tissue ; Pancreatic beta cell ; Gene regulation ; Epigenome

Team contact

Jean-Sébastien Annicote
Group leader

jean-sebastien.annicotte@inserm.fr
03 20 97 42 54