Epigenetic modifications in the GH-dependent Prlr, Hnf6, Cyp7b1, Adh1 and Cyp2a4 genes.

Many sex differences in liver gene expression originate in the brain, depend on GH secretion and may underlie sex disparities in hepatic disease. Because epigenetic mechanisms may contribute, we studied promoter methylation and microRNA abundance in the liver, associated with expression of sexual dimorphic genes in mice with selective disruption of the dopamine D2 receptor in neurons (neuroDrd2KO), which decreases hypothalamic Ghrh, pituitary GH, and serum IGFI and in neonatally androgenized female mice which have increased pituitary GH content and serum IGFI. We evaluated mRNA levels of the female predominant genes prolactin receptor (Prlr), alcohol dehydrogenase 1 (Adh1), Cyp2a4, and hepatocyte nuclear transcription factor 6 (Hnf6) and the male predominant gene, Cyp7b1.

Brain Control of Sexually Dimorphic Liver Function and Disease: The Endocrine Connection.

A multistep signaling cascade originates in brain centers that regulate hypothalamic growth hormone-releasing hormone (Ghrh) and somatostatin expression levels and release to control the pattern of GH secretion. This process is sexually fine-tuned, and relays important information to the liver where GH receptors can be found. The temporal pattern of pituitary GH secretion, which is sex-specific in many species (episodic in males and more stable in females), represents a major component in establishing and maintaining the sexual dimorphism of hepatic gene transcription.

Pituitary and brain dopamine D2 receptors regulate liver gene sexual dimorphism.

Liver sexual gene dimorphism, which depends mainly on specific patterns of GH secretion, may underlie differential susceptibility to some liver diseases. Because GH and prolactin secretion are regulated by dopaminergic pathways, we studied the participation of brain and lactotrope dopamine 2 receptors (D2Rs) on liver gene sexual dimorphism, to explore a link between the brain and liver gene expression. We used global D2R knockout mice (Drd2(-/-)) and conducted a functional dissection strategy based on cell-specific Drd2 inactivation in neurons (neuroDrd2KO) or pituitary lactotropes.

Selective disruption of dopamine D2 receptors in pituitary lactotropes increases body weight and adiposity in female mice.

Prolactin, a pleiotropic hormone secreted by lactotropes, has reproductive and metabolic functions. Chronically elevated prolactin levels increase food intake, but in some hyperprolactinemic states such as in the global dopamine D2 receptor (D2R) knockout mouse, food intake is not increased. Here, we conduct a cell-specific genetic dissection study using conditional mutant mice that selectively lack D2Rs from pituitary lactotropes (lacDrd2KO) to evaluate the role of elevated prolactin levels without any confounding effect of central D2Rs on motor and reward mechanisms related to food intake.

Expression and methylation status of female-predominant GH-dependent liver genes are modified by neonatal androgenization in female mice.

Neonatal androgenization masculinizes the GH axis and thus may impact on liver gene regulation. Neonatal testosterone administration to female mice decreased (defeminized) female predominant GH-dependent liver gene expression (Hnf6, Adh1, Prlr, Cyp3a41) and did not modify male predominant genes (Cyp7b1, Cyp4a12, Slp). Female predominance of Cis mRNA, an inhibitor of episodic GH signaling pathway, was unaltered.

Neonatal xenoestrogen exposure alters growth hormone-dependent liver proteins and genes in adult female rats.

The hypothalamic-growth hormone (GH)-liver axis represents a new concept in endocrine regulation of drug toxicity. Preponderant sex differences are found in liver gene expression, mostly dependent on the sexually dimorphic pattern of GH secretion which is set during the neonatal period by gonadal steroids. We tested if GH-dependent sexually dimorphic liver enzymes and proteins was perturbed by neonatal Bisphenol A (BPA) treatment in female rats.

New insights into the endocrine and metabolic roles of dopamine D2 receptors gained from the Drd2 mouse.

Dopamine D2 receptor (D2R) participation in prolactin regulation is well documented, but the role of D2Rs in the control of other hormones involved in growth, food intake and glucose metabolism has not been extensively studied. The study of D2R knockout mice (Drd2(-/-)) puts forward new insights into the role of the D2R in growth hormone (GH)-releasing hormone-GH regulation, peptides involved in food intake, glucose homeostasis, as well as in prolactinoma development. The expected phenotype of chronic hyperprolactinemia and prolactinoma development was found in the Drd2(-/-) mouse, and this model constitutes a valuable tool in the study of dopamine-resistant prolactinomas.

Differential neonatal testosterone imprinting of GH-dependent liver proteins and genes in female mice.

Abnormal exposure to steroid hormones within a critical developmental period elicits permanent alterations in female reproductive physiology in rodents, but the impact on the female GH axis and the underlying sexual differences in hepatic enzymes have not been described in detail. We have investigated the effect of neonatal androgenization of female mice (achieved by s.c.