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    Equipe : AMPK et kinases apparentées à l'AMPK dans la physiopathologie du diabète et de l'obésité

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    The central goal of our research is to elucidate the pathophysiological role of the conserved signal transduction pathways controlled by the energy sensor AMPK (AMP-activated protein kinase) and the member of the AMPK-related protein kinase family SIK (Salt-Induced Kinase) in health and diseases.

     

    Responsable :

     

     

    Our ongoing studies are designed to demonstrate the potential of AMPK and SIK signaling pathways as therapeutic targets to reverse the metabolic abnormalities associated with type 2 diabetes and obesity.

     

    Objectives

    Our research strategy is to discover the key cellular processes governed by AMPK and SIK by using tissue-specific knockout mouse models and genetically modified cell lines with the CRISPR-Cas9 technology; our general objective is to identify and validate target proteins and genes by molecularly interrogating established in vivo and in vitro experimental models (through multi-omics analysis), and to propose specific therapeutic approaches by genetic and pharmacological means. Our current efforts are aimed at deciphering the function of AMPK in gastrointestinal tract (Axis 1) and exploring the role of SIK  in the regulation of hepatic glucose production (Axis 2) and assess their utility in diagnosis and efficacy in therapeutics for type 2 diabetes and obesity. The impact of our research will be relevant not only for the purpose of growing scientific knowledge but also for its translation into new therapeutic strategies.

     

    Axis 1 - Targeting AMPK for the control of intestinal epithelial barrier integrity

    Principal investigator : Benoit VIOLLET

    benoit.viollet@inserm.fr

    Tel : 33(0)1-44-41-24-01

     

    Context

    In recent years, obesity has become a major threat to human health and well-being. A widely accepted explanation for the increasing prevalence of obesity lays on the imbalance between energy intake and energy expenditure. As prevalence continues to rise and economic costs also escalate, innovative management strategies beyond primary prevention and traditional lifestyle interventions are urgently needed. Recent advances emphasize the impairment of gut epithelial barrier function as a contributing factor, in conjunction with excessive energy intake. In animal models of obesity, permeability of the intestine is increased because of impairment of tight junction (TJ) proteins, allowing translocation of bacterial endotoxin, resulting in low-grade systemic inflammation and insulin resistance. Energy metabolism of epithelial cells is essential for maintaining the structure and function of the intestinal epithelial barrier. Rupture of intestinal epithelial barrier (IEB) integrity is associated with a variety of gastrointestinal disorders. In particular IEB permeability is increased with obesity and inflammatory bowel disease and strengthening of the IEB has been associated with better clinical outcomes.

     

    Background

    To sustain metabolism, intracellular ATP concentration must be regulated within an appropriate range. This coordination is achieved through the function of the AMP-activated protein kinase (AMPK), a cellular “fuel gauge”. Once activated by falling energy charge, AMPK responds by stimulating energy production via catabolic pathways whilst decreasing non-essential energy consuming pathways to restore cellular energy stores. Thus, AMPK represents a point of conversion of regulatory signals monitoring systemic and cellular energy status. Although there is a robust correlation between AMPK and the metabolic control in metabolic tissue such as liver and skeletal muscle, the role of the AMPK activity in other organs is less studied. The gut is an important sensor of energy balance and nutrient status and, as such, signals to the brain and periphery via neurons and hormones. AMPK has been involved in the gut-restricted glucose-lowering actions of metformin, triggering GLP-1R to influence a gut-brain axis. Metformin is the oldest and most commonly prescribed oral glucose-lowering medication worldwide and is considered a first-line therapy for newly diagnosed patients. Nevertheless, the glucose-lowering mechanisms of action of metformin continue to be explored and debated despite more than 50 years of clinical experience. Recent evidences also indicate that AMPK may fulfill key functions for the maintenance of IEB integrity but the mechanisms are still poorly understood. Therefore, a more comprehensive analysis of AMPK function in the gastrointestinal tract is needed to uncode the precise effects of AMPK activation on IEB properties and response to metformin.

     

    Objectives

    The overall objective of this project is to study the role of AMPK in the maintenance of IEB homeostasis and in metformin gut-restricted action. The specific aims are 1) to explore the impact of AMPK dysregulation on IEB rupture and development inflammation; 2) to validate strategies of IEB strengthening or restoration by activation of AMPK ; 3) to evaluate the precise contribution of AMPK in metformin gut-restricted action. Our project will combine molecular and functional analyzes of human pathological/control samples to examination of mice model developing low or high grade chronic inflammation with or without AMPK activation in epithelial cells.

     Model of AMPK-dependent regulation of epithelial intestinal cell tight junction assembly

     

    Axis 2 -  Role of SIK in hepatic glucose production control and therapeutic potential in type 2 diabetes mellitus

    Principal investigator : Marc FORETZ

    marc.foretz@inserm.fr

    Tel : 33(0)1-44-41-24-38

     

    Context

                Type 2 diabetes prevalence has dramatically increased both in industrialized and emerging countries. Type 2 diabetic patients are unable to maintain effective long term control of their hyperglycemia, thus placing them at elevated risk of developing microvascular and macrovascular complications. These complications significantly impact patients’ quality of life and also place substantial burden on healthcare systems. Therefore, the discovery of new targets to curb excessive endogenous glucose production in type 2 diabetic patients is a major issue, especially in patients refractory to conventional antidiabetic treatments. One increasingly attractive molecular target is the salt-induced kinase (SIKs) family, which has emerged recently as novel regulator of gluconeogenesis in the liver.

     

    Background

                SIKs belong to the AMP-protein activated (AMPK)-related kinase family, which are activated following the phosphorylation of their T-loop threonine residue by the master kinase LKB1. We have previously shown that the LKB1-SIKs pathway functions as a key gluconeogenic gatekeeper for hepatic glucose production by keeping the gluconeogenic program repressed. SIKs suppresses gluconeogenic gene expression via the phosphorylation of cAMP-regulated transcriptional coactivators (CRTCs) and class IIa histone deacetylases (HDACs), which are then sequestered in the cytoplasm. In response to fasting/glucagon, the activity of hepatic SIKs is inhibited by multiple phosphorylations outside of the catalytic T-loop by the protein kinase A (PKA), leading to CRTCs and class IIa HDACs dephosphorylation, which then translocate to the nucleus and induce gluconeogenic gene expression. Some studies have suggested that SIKs activity is decreased in the liver of diabetic mice, suggesting that a loss of SIK activity might be involved in the pathophysiology of type 2 diabetes.

     

    Objectives

                Our first objective is to analyze the role of SIKs in the control of hepatic gluconeogenesis through the generation and the use of new tissue-specific SIK knockout mouse models using the Cre/loxP system. Our second objective is to study the in vitro and in vivo consequences of SIK activation on gluconeogenesis by using gain-of-function approaches in the context of type 2 diabetes. These studies should provide new insights into the role of SIK in the regulation of gluconeogenesis and unravel novel targets for the treatment of diabetes.

     

    Model of SIK-dependent gluconeogenesis regulation in liver

     

     Mains Publications

     

    Research articles:

     

     - Glucose availability but not changes in pancreatic hormones sensitizes hepatic AMPK activity during nutritional transition in rodents. Huet C, Boudaba N, Guigas B, Viollet B, Foretz M. J. Biol. Chem. 2020 Mar 17. pii: jbc.RA119.010244. doi: 10.1074/jbc.RA119.010244.

     - AMPK Activation Promotes Tight Junction Assembly in Intestinal Epithelial Caco-2 Cells. Olivier S, Leclerc J, Grenier A, Foretz M, Tamburini J, Viollet B. Int J Mol Sci. 2019 Oct 18;20(20). pii: E5171.

     - AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation In Vivo. Foretz M, Even PC, Viollet B. Int J Mol Sci. 2018 Sep 19;19(9). pii: E2826.

     - AMPK Re-Activation Suppresses Hepatic Steatosis but its Downregulation Does Not Promote Fatty Liver Development. Boudaba N, Marion A, Huet C, Pierre R, Viollet B, Foretz M. EBioMedicine. 2018 Feb;28:194-209.

     - The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. Patel, K., M. Foretz, A. Marion, D.G. Campbell, R. Gourlay, N. Boudaba, E. Tournier, P. Titchenell, M. Peggie, M. Deak, M. Wan, K.H. Kaestner, O. Goransson, B. Viollet, N.S. Gray, M.J. Birnbaum, C. Sutherland, and K. Sakamoto. Nat Commun. 2014 Aug 4;5:4535.

    Press release : http://archives.cnrs.fr/insb/article/2014/m-foretz

     

    Review articles:

     

     - Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Foretz M, Guigas B, Viollet B. Nat Rev Endocrinol. 2019 Oct;15(10):569-589.

     - Salt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential. Wein MN, Foretz M, Fisher DE, Xavier RJ, Kronenberg HM. Trends Endocrinol Metab. 2019 Jun;30(6):407.

     - Promise and challenges for direct small molecule AMPK activators. Olivier S, Foretz M, Viollet B. Biochem Pharmacol. 2018 Jul;153:147-158.

     

    Team's news

     

    2020 - Organization of the 11th International Meeting on AMPK : AMPK and AMPK-related kinases: from biological action to new therapies - Sept 27- Oct 1, 2020 - Evian-Les-Bains, France.

    Click here to register

     2020 - Edition of the "AMP-activated protein kinase signalling 2.0 - Special Issue" - International Journal of Molecular Science.

     2020 - Edition of the Research Topic on “AMPK and mTOR Beyond Signaling: Emerging Roles in Transcriptional Regulation“ - Frontiers in Cell and Developmental Biology.

     2018 - Edition of the Research Topic on “Metformin: Beyond Diabetes"
- Frontiers in Endocrinology.

    Click here to download Ebook PDF

     2018 - Edition of the "AMP-activated protein kinase signalling - Special Issue" - International Journal of Molecular Science.

    Click here to download Ebook PDF

     2017 – Organization of the 3rd European Workshop on AMPK -  Sept 10-13, 2017 – Ile de Porquerolles, France.

     

    Financial supports