Pituitary and Brain Dopamine D2 Receptors Regulate Liver Gene Sexual Dimorphism

MARIA CECILIA RAMIREZ, ANA MARIA ORNSTEIN, GUILLERMINA MARIA LUQUE, MARIA INES PEREZ MILLAN, ISABEL GARCIA-TORNADU, MARCELO RUBINSTEIN, AND DAMASIA BECU-VILLALOBOS

ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2015 vol. 156 p. 1040 - 1051

0013-7227

Liver sexual gene dimorphism, which depends mainly on specific patterns of GH secretion, mayunderlie differential susceptibility to some liver diseases. Because GH and prolactin secretion areregulated by dopaminergic pathways, we studied the participation of brain and lactotrope dopamine2 receptors (D2Rs) on liver gene sexual dimorphism, to explore a link between the brainand liver gene expression. We used global D2R knockout mice (Drd2/) and conducted a functionaldissection strategy based on cell-specific Drd2 inactivation in neurons (neuroDrd2KO) orpituitary lactotropes. Disruption of neuronal D2Rs (which impaired the GH axis) decreased most ofmale or female-predominant class I liver genes and increased female?predominant class II genesin males, consistent with the positive (class I) or negative (class II) regulation of these genes by GH.Notably, sexual dimorphism was lost for class I and II genes in neuroDrd2KO mice. Disruption oflactotrope D2Rs did not modify class I or II genes in either sex, because GH axis was preserved. Butsurprisingly, 1 class II gene (Prlr) and female-predominant class I genes were markedly up-regulatedin lacDrd2KO females, pointing to direct or indirect effects of prolactin in the regulation of selectedfemale-predominant liver genes. This suggestion was strengthened in the hyperprolactinemicDrd2/ female mouse, in which increased expression of the same 4 liver genes was observed,despite a decreased GH axis. We hereby demonstrate endocrine-mediated D2R actions on sexualdimorphic liver gene expression, which may be relevant during chronic dopaminergic medicationsin psychiatric disease