Folate and Cobalamin Deficiencies during Pregnancy Disrupt the Glucocorticoid Response in Hypothalamus through -Homocysteinilation of the Glucocorticoid Receptor.
Fiche publication
Date publication
juin 2023
Journal
International journal of molecular sciences
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GUEANT Jean-Louis
Tous les auteurs :
Michel A, Kokten T, Saber-Cherif L, Umoret R, Alberto JM, Helle D, Julien A, Daval JL, Guéant JL, Bossenmeyer-Pourié C, Pourié G
Lien Pubmed
Résumé
Vitamin B9 (folate)/B12 (cobalamin) deficiency is known to induce brain structural and/or functional retardations. In many countries, folate supplementation, targeting the most severe outcomes such as neural tube defects, is discontinued after the first trimester. However, adverse effects may occur after birth because of some mild misregulations. Various hormonal receptors were shown to be deregulated in brain tissue under these conditions. The glucocorticoid receptor (GR) is particularly sensitive to epigenetic regulation and post-translational modifications. In a mother-offspring rat model of vitamin B9/B12 deficiency, we investigated whether a prolonged folate supplementation could restore the GR signaling in the hypothalamus. Our data showed that a deficiency of folate and vitamin B12 during the in-utero and early postnatal periods was associated with reduced GR expression in the hypothalamus. We also described for the first time a novel post-translational modification of GR that impaired ligand binding and GR activation, leading to decrease expression of one of the GR targets in the hypothalamus, AgRP. Moreover, this brain-impaired GR signaling pathway was associated with behavioral perturbations during offspring growth. Importantly, perinatal and postnatal supplementation with folic acid helped restore GR mRNA levels and activity in hypothalamus cells and improved behavioral deficits.
Mots clés
corticoid pathway, fetal programming, hypothalamus, one-carbon metabolism, post-translational modification
Référence
Int J Mol Sci. 2023 06 7;24(12):