Folate and Cobalamin Deficiencies during Pregnancy Disrupt the Glucocorticoid Response in Hypothalamus through N-Homocysteinilation of the Glucocorticoid Receptor

Author:

Michel Arnaud1,Kokten Tunay1,Saber-Cherif Lynda1ORCID,Umoret Rémy1ORCID,Alberto Jean-Marc1,Helle Déborah1,Julien Amélia1,Daval Jean-Luc1,Guéant Jean-Louis12ORCID,Bossenmeyer-Pourié Carine1,Pourié Grégory1ORCID

Affiliation:

1. Inserm UMRS 1256 NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, F-54000 Nancy, France

2. National Center of Inborn Errors of Metabolism, University Regional Hospital of Nancy, F-54000 Nancy, France

Abstract

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.

Funder

Inserm

University of Lorraine

CHRU Nancy

FHU ARRIMAGE

French Agence Nationale de la Recherche

PIA project

Lorraine Université d’Excellence

OMAGE

region GrandEST of France

FEDER

European Union

French Ministry of Higher Education

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference61 articles.

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