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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

Dr Anne-Catherine Maurin

Anne-Catherine Maurin's profile

Field of research

Adaptive mechanisms to an amino acid imbalance stress

Among the 20 amino acids (AA) used for protein synthesis, 9 AA cannot be synthesized de novo and are called are indispensable AA (IAA): valine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, histidine and tryptophan. Furthermore, there is no specific system for storing AA. Consequently, when necessary the organism must hydrolyze endogenous protein to produce free amino acids, at the expense of essential elements.

One stressful condition for the organism is represented by an imbalanced supply of AA in the diet, notably in case of inadequate IAA inputs. Indeed, while the supply of nutrients in the meal is supposed to trigger biosynthesis, the lack of one or several AA hinders anabolic processes. In addition to nutritional factors, various forms of stress (trauma, thermal burn, sepsis, fevers, etc.) or several chronic illnesses (cancer, AIDS, chronic renal, cardiac, hepatic, and pulmonary diseases…) can affect nitrogen metabolism. In such a situation, changes in the patterns of free amino acids are observed in plasma and urine. Therefore, some signalling pathways exist that can detect AA deficits and trigger adaptive processes in order to limit the deleterious effects.

Our goal is to determine how this adaptation takes place, by identifying

1) the molecular mechanisms involved and

2) the cellular and physiological functions that are modulated in response to a nutritional stress.

Research activities

Physiological functions regulated by the GCN2/p-eIF2a/ATF4 pathway

Control of food intake: Omnivorous animals are able to recognize food sources exhibiting IAA imbalances: they will consume substantially less of an otherwise identical meal lacking a single IAA and will search for healthier balanced diets. We have shown that in response to an IAA devoid meal, the brain-specific activation of GCN2 leads to food intake inhibition. More precisely, we have shown that GCN2 activity in the mediobasal hypothalamus controls the onset of the aversive response. Importantly, the sole phosphorylation of eIF2a in this area is sufficient to dramatically inhibit food intake. In addition, rodents have the innate ability to compose a balanced diet from different sources of macronutrients, particularly adapting the protein consumption level to their needs. We have shown that mice change their macronutrient selection profile during ageing and that this phenotype is significantly affected by GCN2 ablation (GCN2 -/- mice greatly reduce their consumption of proteins in favor of lipids).

Autophagy regulation: Animals respond to dietary IAA deficiencies by hydrolyzing body protein in order to produce free AA and maintain their homeostasis. The first tissue to hydrolyze resident protein when AA content is limited is the liver, through the up-regulation of autophagy. Following the consumption of a meal deficient in one IAA, the corresponding IAA concentration in the blood drops rapidly and to a great extent, leading to the activation of the GCN2/p-eIF2a/ATF4 pathway, notably in the liver. Our results show that activation of the GCN2/p-eIF2a/ATF4 pathway is involved in the signaling events of autophagy up-regulation following a lack of IAA.

Publications

Gietzen DW, Anthony TG, Fafournoux P, Maurin AC, Koehnle TJ, Hao S. (2016) Measuring the ability of mice to sense dietary essential amino acid deficiency: the importance of amino acid status and timing. Cell Reports. 16:2049-2050.

Chaveroux C, Bruhat A, Carraro V, Jousse C, Averous J, Maurin AC, Parry L, Mesclon F, Muranishi Y, Cordelier P, Meulle A, Baril P, Do Thi A, Ravassard P, Mallet J, Fafournoux P. (2016) Regulating the expression of therapeutic transgenes by controlled intake of dietary essential amino acids. Nature Biotechnology 34(7):746-51.

Maurin A C, Benani A, Lorsignol A, Brenachot X, Parry L, Carraro V, Guissard C, Averous J, Jousse C, Bruhat A, Chaveroux C, B'Chir W, Muranishi Y, Ron D, Penicaud L and Fafournoux P. (2014) Hypothalamic eIF2alpha signaling regulates food intake. Cell Reports 6:438-444.

B'Chir W, Maurin A C, Carraro V, Averous J, Jousse C, Muranishi Y, Parry L, Stepien G, Fafournoux P and Bruhat A. (2013) The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic acids research 41: 7683-7699.

Maurin A C, Chaveroux C, Lambert-Langlais S, Carraro V, Jousse C, Bruhat A, Averous J, Parry L, Ron D, Alliot J and Fafournoux P. (2012) The amino acid sensor GCN2 biases macronutrient selection during aging. European journal of nutrition 51: 119-126.

Carraro V, Maurin A C, Lambert-Langlais S, Averous J, Chaveroux C, Parry L, Jousse C, Ord D, Ord T, Fafournoux P and Bruhat A. (2010) Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2alpha/ATF4 pathway. PLoS One 5: e15716.

Jousse C, Deval C, Maurin AC, Parry L, Chérasse Y, Chaveroux C, Lefloch R, Lenormand P, Bruhat A and Fafournoux P. (2007) TRB3 inhibits the transcriptional activation of stress-regulated genes by a negative feedback on the ATF4 pathway. Journal of Biological Chemistry 282:15851-61.

Maurin AC, Jousse C, Averous J, Parry L, Bruhat A, Cherasse Y, Zeng H, Zhang Y, Harding HP, Ron D and Fafournoux P. (2005) The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores. Cell Metabolism 1:273-7.

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