Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Folate and Vitamin B12 Gestational Deficiency Disturb Glucocorticoid Response in Hypothalamus Through N-Homocysteinilation of the Glucocorticoid Receptor

Arnaud Michel
,
Tunay Kokten
,
Lynda Saber Cherif
ORCID logo ,
Rémy Umoret
ORCID logo ,
Jean-Marc Alberto
,
Déborah Helle
,
Amélia Julien
,
Daval Jean-Luc
,
Jean-Louis Guéant
ORCID logo ,
Carine Bossenmeyer-Pourié
* ,
Grégory Pourié
ORCID logo
Version 1 : Received: 14 April 2023 / Approved: 17 April 2023 / Online: 17 April 2023 (03:28:12 CEST)

A peer-reviewed article of this Preprint also exists.

Michel, A.; Kokten, T.; Saber-Cherif, L.; Umoret, R.; Alberto, J.-M.; Helle, D.; Julien, A.; Daval, J.-L.; Guéant, J.-L.; Bossenmeyer-Pourié, C.; Pourié, G. Folate and Cobalamin Deficiencies during Pregnancy Disrupt the Glucocorticoid Response in Hypothalamus through N-Homocysteinilation of the Glucocorticoid Receptor. Int. J. Mol. Sci. 2023, 24, 9847. Michel, A.; Kokten, T.; Saber-Cherif, L.; Umoret, R.; Alberto, J.-M.; Helle, D.; Julien, A.; Daval, J.-L.; Guéant, J.-L.; Bossenmeyer-Pourié, C.; Pourié, G. Folate and Cobalamin Deficiencies during Pregnancy Disrupt the Glucocorticoid Response in Hypothalamus through N-Homocysteinilation of the Glucocorticoid Receptor. Int. J. Mol. Sci. 2023, 24, 9847.

Abstract

Vitamin B9(folate)/B12 deficiency is known to induce brain structural and/or functional retardations. Besides neural tube defects in case of major consequences, several mild deregulations also lead to deleterious effect after birth, and folate supplementation recommended in some countries usually stop at the end of the first trimester. Various hormonal receptors were shown to be deregulated in brain tissue under this context. The glucocorticoid receptor (GR) is particularly sensitive to epigenetic regulation and post-traductional modifications. In a mother-offspring rat model of vitamin B9/B12 deficiency, we investigated whether a prolonged folate supplementation could restore the GR signalization in the hypothalamus. Our data showed that a deficiency in folate and vitamin B12 during the in-utero and the early postnatal periods was associated with reduced GR expression inn the hypothalamus. We also described for the first time a new post-traductional modification of GR that impaired ligand binding and GR activation, leading to decreased the expression of one of the GR targets in the hypothalamus, AgRP. Moreover, this brain-impaired GR pathway was associated with behavioral perturbations during offspring growth. Importantly, perinatal and postnatal supplementation with folic acid helped restore GR mRNA level and activity in hypothalamus cells and improved behavioral deficits.

Keywords

brain maturation; glucocorticoid receptor; post-traductional modification; one-carbone metabolism; homocysteine

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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