Neural growth hormone: regional regulation by estradiol and/or sex chromosome complement in male and female mice - PubMed (original) (raw)

Neural growth hormone: regional regulation by estradiol and/or sex chromosome complement in male and female mice

Kayla M Quinnies et al. Biol Sex Differ. 2015.

Abstract

Background: Sex differences in pituitary growth hormone (GH) are well documented and coordinate maturation and growth. GH and its receptor are also produced in the brain where they may impact cognitive function and synaptic plasticity, and estradiol produces Gh sex differences in rat hippocampus. In mice, circulating estradiol increases Gh mRNA in female but not in male medial preoptic area (mPOA); therefore, additional factors regulate sexually dimorphic Gh expression in the brain. Thus, we hypothesized that sex chromosomes interact with estradiol to promote sex differences in GH. Here, we assessed the contributions of both estradiol and sex chromosome complement on Gh mRNA levels in three large brain regions: the hippocampus, hypothalamus, and cerebellum.

Methods: We used the four core genotypes (FCG) mice, which uncouple effects of sex chromosomes and gonadal sex. The FCG model has a deletion of the sex-determining region on the Y chromosome (Sry) and transgenic insertion of Sry on an autosome. Adult FCG mice were gonadectomized and given either a blank Silastic implant or an implant containing 17β-estradiol. Significant differences in GH protein and mRNA were attributed to estradiol replacement, gonadal sex, sex chromosome complement, and their interactions, which were assessed by ANOVA and planned comparisons.

Results: Estradiol increased Gh mRNA in the cerebellum and hippocampus, regardless of sex chromosome complement or gonadal sex. In contrast, in the hypothalamus, females had higher Gh mRNA than males, and XY females had more Gh mRNA than XY males and XX females. This same pattern was observed for GH protein. Because the differences in Gh mRNA in the hypothalamus did not replicate prior studies using other mouse models and tissue from mPOA or arcuate nucleus, we examined GH protein in the arcuate, a subdivision of the hypothalamus. Like the previous reports, and in contrast to the entire hypothalamus, a sex chromosome complement effect showed that XX mice had more GH than XY in the arcuate.

Conclusions: Sex chromosome complement regulates GH in some but not all brain areas, and within the hypothalamus, sex chromosomes have cell-specific actions on GH. Thus, sex chromosome complement and estradiol both contribute to GH sex differences in the brain.

Keywords: Cerebellum; Estradiol; Growth hormone; Growth hormone-releasing hormone; Hypothalamus; Obesity; Sex chromosomes; Sex differences.

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Figures

Figure 1

Figure 1

Gh mRNA in (A) the cerebellum, showing a significant increase in the relative quantity (RQ) of Gh mRNA in estradiol-treated animals of all genotypes; (B) the hippocampus, a significant effect of estradiol on Gh RQ was noted; and (C) the hypothalamus where effects of both sex chromosomes and gonadal sex were observed. Adult mice from the four core genotypes—XY males (black bars), XX males (horizontal striped bars), XX females (white bars), and XY females (diagonal striped bars)—were gonadectomized and treated with estradiol (E) or given empty implants. For the cerebellum: blank: XYM N = 7, XXM N = 7, XXF N = 6, XYF N = 7; E2: XYM N = 6, XXM N = 8, XXF N = 4, XYF N = 5. In the hippocampus: blank: XYM N = 6, XXM N = 7, XXF N = 6, XYF N = 5; E2: XYM N = 9, XXM N = 8, XXF N = 6, XYF N = 6. In the hypothalamus: N = 6 for all groups. The single asterisks indicate significant effect of estradiol (P < 0.05). The double asterisks indicate significant sex difference (P < 0.05). The plus symbols indicate mice in the XY male group which are significantly different from mice in the XX male and XY female groups (P < 0.05).

Figure 2

Figure 2

GH protein in the hypothalamus. (A) A representative blot is shown. (B) Densitometry data from the blots is presented. Adult mice from the four core genotypes—XY males (XYM N = 4, black bars), XX males (XXM N = 3, horizontal striped bars), XX females (XXF N = 3, white bars), and XY females (XYF N = 3, diagonal striped bars)—were gonadectomized and treated with estradiol (E). The single asterisk denotes significant effect of sex chromosome complement (P < 0.05). The double asterisks denote significant effect of gonadal sex (P < 0.05). The plus symbol denotes XY females which are significantly different from all other groups (P < 0.05).

Figure 3

Figure 3

GH protein in the arcuate nucleus of the hypothalamus. (A) A representative blot is shown. (B) Densitometry data from the blots is presented. Adult mice from the four core genotypes—XY males (black bars), XX males (horizontal striped bars), XX females (white bars), and XY females (diagonal striped bars)—were gonadectomized and treated with estradiol (E). N = 6 in each group. The single asterisk signifies significant effect of sex chromosome complement (P < 0.05).

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