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    Team: Insulin signaling, glucose sensing and glucotoxicity

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    Team leaders:

     

     

    Alteration of energy balance is a cornerstone in the development of metabolic diseases such as type 2 diabetes and obesity, the prevalence of which is steadily increasing all over the world. Our team is interested in the cellular and molecular mechanisms involved in the control of energy homeostasis. More specifically, we aim at understanding how genetic and environmental modifications may affect biological functions, leading to the development of these pathologies.

     

    Objectives

     

    Insulin, secreted by the beta-cells of the pancreas in response to food intake, plays a major role in the regulation of energy metabolism, through fine-tuning of nutrient utilisation and storage in different tissues. Our team aims at better characterizing the molecular and cellular mechanisms involved in the regulation of insulin sensitivity, and at elucidating how their perturbation may result in insulin resistance and in the alterations of metabolic pathways that are observed in diabetes, obesity and hepatic steatosis.

     

     

     

     

    To improve our knowledge of the cellular and molecular regulation of insulin and glucose signalling in physiological and pathological conditions, we intend to:

     i) determine the mechanisms involved in the control of fatty acid synthesis through hepatic lipogenesis, in physiological conditions as well as in hepatic diseases (NAFLD);

     ii) evaluate the contribution of glucose metabolism in liver/pancreas and intestine/pancreas inter-organ dialogues;

     iii) analyse insulin signalling mechanisms involved in the metabolic and mitogenic effects of the hormone;

     iv) study the role of O-GlcNAcylation (a reversible post-translational modification induced by hyperglycaemia) in the regulation of cell signalling and in the glucotoxicity phenomenon in hepatocytes, pancreatic beta-cells and macrophages;

     v) establish new tools, based on the BRET technology, for the study of protein-protein interactions in living cells, and for the development of high-throughput screening assays for drug discovery;

     Altogether, our studies aim at identifying new therapeutic targets in the context of metabolic diseases.

     

    Main publications

     

    • Perdereau, D., Cailliau, K., Browaeys-Poly, E., Lescuyer, A., Carre, N., Benhamed, F., Goenaga, D., Burnol, A. F. Insulin-induced cell division is controlled by the adaptor Grb14 in a Chfr-dependent manner Cell Signal 2015; 27(4):798-806
    • Fardini, Y., Masson, E., Boudah, O., Ben Jouira, R., Cosson, C., Pierre-Eugene, C., Kuo, M. S., Issad, T. O-GlcNAcylation of FoxO1 in pancreatic beta cells promotes Akt inhibition through an IGFBP1-mediated autocrine mechanism FASEB J 2014; 28(2):1010-21
    • Kuo, M-S., Auriau, J., Pierre-Eugene, C., Issad, T. Development of a Human Breast-Cancer Derived Cell Line Stably Expressing a Bioluminescence Resonance Energy Transfer (BRET)-Based Phosphatidyl Inositol-3 Phosphate (PIP3) Biosensor. PLoS ONE 2014; 9(3):e92737
    • Filhoulaud, G., Guilmeau, S., Dentin, R., Girard, J., Postic, C. Novel insights into ChREBP regulation and function Trends Endocrinol Metab 2013; 24(5):257-68
    • Benhamed, F., Denechaud, P. D., Lemoine, M., Robichon, C., Moldes, M., Bertrand-Michel, J., Ratziu, V., Serfaty, L., Housset, C., Capeau, J., Girard, J., Guillou, H., Postic, C. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans J Clin Invest 2012; 122(6):2176-94