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INRA
24, chemin de Borde Rouge –Auzeville – CS52627
31326 Castanet Tolosan CEDEX - France

Dernière mise à jour : Mai 2018

Menu Logo Principal logo Université Clermont Auvergne & associés

Human Nutrition Unit

Zone de texte éditable et éditée et rééditée

Alain Bruhat

  BRUHAT-Alain                                           

Tel : +33(0)4 73 62 41 50
E-mail: alain.bruhat[at]inrae.fr


Nutrition represents not only the absorption of food but also the metabolic fate and the effect of nutrients on various physiological functions. To cope with the highly variable supply of nutrients, higher organisms, and more particularly mammals, have developed complex mechanisms capable of dampening the effect of these fluctuations. In particular, certain nutritional situations (protein under-nutrition, etc.) and/or pathology (burns, infections, cancers, etc.) result in a strong variation in the blood concentration of amino acids (AA). Given that some AAs (i) cannot be synthesized by the body (9 AA are essential) and (ii) that there is no dedicated storage system as is the case for lipids or glucose, the organism has to adapt to an essential AA deficiency (AAI). For that, certain physiological functions have to be regulated (growth, appetite…). This regulation requires (i) to detect the AAI deficiency and (2) to adjust the level of expression of a number of specific genes involved in the defense processes and/or adaptation to a disease. limitation in AAI. It is now well established that AAIs can regulate physiological functions (food intake, autophagy…) in particular by a direct modulation of the expression of specific target genes via the activation of signaling pathways such as the GCN2-eIF2α-ATF4 pathway.

Initially, my research project allowed me to make a major contribution to the characterization of the GCN2-eIF2α-ATF4 signaling pathway, in particular through the transcriptional mechanisms involved in the process of adaptation to AA deprivation. I was pioneer in the characterization of the first Amino Acid Response Element (AARE) sequence (Bruhat et al, Mol Cell Biol 2000).

Currently, my research projects still concern the eIF2α-ATF4 pathway and aim to: 
1- Study the role of the eIF2α-ATF4 signaling pathway in the regulation of the transcription of genes involved in the autophagic process (B'chir et al, Nucleic Acids Res 2013) (B'chir et al, Cell Signal. 2014).

2- Study the role of the eIF2α-ATF4 signaling pathway in the whole animal as a function of nutritional and pathophysiological situations.
  • (a) Validation of the functionality of the GCN2-eIF2α-ATF4 pathway in vivo in mice (Carraro et al, PLoS One 2010).
  • (b) Generation of a bioluminescent transgenic mouse line (called CARE-LUC) to visualize in real time the activation of the eIF2α-ATF4 pathway (Chaveroux et al, Science Sci 2015).
  • (c) Study of the role of the eIF2α-ATF4 pathway in the metabolic adaptations following chronic treatment with paracetamol and leading to muscle wasting.
  • (d) Using intermittent activation of the GCN2-eIF2α-ATF4 pathway by discontinuous dietary deficiency of sulfur amino acids to reduce the development of obesity. 
3- Develop a gene expression system inducible by a nutritional manipulation via the GCN2-eIF2α-ATF4 pathway and usable in gene therapy. The system comprises an artificial promoter inducible by an AAI deficiency and an AAI deficient food. The objective is to use this tool in gene therapy to control the expression of transgenes of therapeutic interest (Chaveroux et al, Nature Biotech 2016) with applications in the field of cancer and in other pathologies. This project is an integral part of the Research and Development strategy of the NUTRITHERAGENE start-up, of which I am one of the founding members.

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