Hypothalamic eIF2α signaling regulates food intake.
The reversible phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) is a highly conserved signal implicated in the cellular adaptation to numerous stresses such as the one caused by amino acid limitation. In response to dietary amino acid deficiency, the brain-specific activation of the eIF2α kinase GCN2 leads to food intake inhibition. We report here that GCN2 is rapidly activated in the mediobasal hypothalamus (MBH) after consumption of a leucine-deficient diet. Furthermore, knockdown of GCN2 in this particular area shows that MBH GCN2 activity controls the onset of the aversive response. Importantly, pharmacological experiments demonstrate that the sole phosphorylation of eIF2α in the MBH is sufficient to regulate food intake. eIF2α signaling being at the crossroad of stress pathways activated in several pathological states, our study indicates that hypothalamic eIF2α phosphorylation could play a critical role in the onset of anorexia associated with certain diseases.
UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.
Anne-Catherine
AC
Maurin
Centre des Sciences du Goût et de l'Alimentation, UMR 6265-CNRS/1324-INRA, Université de Bourgogne, 21000 Dijon, France.
Alexandre
A
Benani
STROMAlab, UMR 5273-CNRS Université Paul Sabatier, EFS, U1031 INSERM, BP 84225, 31432 Toulouse Cedex 4, France.
Anne
A
Lorsignol
Centre des Sciences du Goût et de l'Alimentation, UMR 6265-CNRS/1324-INRA, Université de Bourgogne, 21000 Dijon, France.
Xavier
X
Brenachot
UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.
Laurent
L
Parry
UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.
Valérie
V
Carraro
STROMAlab, UMR 5273-CNRS Université Paul Sabatier, EFS, U1031 INSERM, BP 84225, 31432 Toulouse Cedex 4, France.
Christophe
C
Guissard
UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.
Julien
J
Averous
UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.
Céline
C
Jousse
UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.
Alain
A
Bruhat
UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.
Cédric
C
Chaveroux
UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.
Wafa
W
B'chir
UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.
Yuki
Y
Muranishi
University of Cambridge, Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Center, Cambridge CB2 0QQ, UK.
David
D
Ron
Centre des Sciences du Goût et de l'Alimentation, UMR 6265-CNRS/1324-INRA, Université de Bourgogne, 21000 Dijon, France.
Luc
L
Pénicaud
UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France. Electronic address: pierre.fafournoux@clermont.inra.fr.
Pierre
P
Fafournoux
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D004435:Eating / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007031:Hypothalamus / Q000378:metabolism*; D007930:Leucine / Q000172:deficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
D015852:Eukaryotic Initiation Factor-2; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D007930:Leucine