Sensitivity of pituitary gonadotropes to hyperglycemia leads to epigenetic aberrations and reduced follicle‐stimulating hormone levels

Abstract

The connection between metabolism and reproductive function is well recognized, and we hypothesized that the pituitary gonadotropes, which produce luteinizing hormone and follicle-stimulating hormone (FSH), mediate some of the effects directly via insulin-independent glucose transporters, which allow continued glucose metabolism during hyperglycemia. We found that glucose transporter 1 is the predominant glucose transporter in primary gonadotropes and a gonadotrope precursor-derived cell line, and both are responsive to culture in high glucose; moreover, metabolite levels were altered in the cell line. Several of the affected metabolites are cofactors for chromatin-modifying enzymes, and in the gonadotrope precursor-derived cell line, we recorded global changes in histone acetylation and methylation, decreased DNA methylation, and increased hydroxymethylation, some of which did not revert to basal levels after cells were returned to normal glucose. Despite this weakening of epigenetic-mediated repression seen in the model cell line, FSH β-subunit ( Fshb) mRNA levels in primary gonadotropes were significantly reduced, apparently due in part to increased autocrine/paracrine effects of inhibin. However, unlike thioredoxin interacting protein and inhibin subunit α, Fshb mRNA levels did not recover after the return of cells to normal glucose. The effect on Fshb expression was also seen in 2 hyperglycemic mouse models, and levels of circulating FSH, required for follicle growth and development, were reduced. Thus, hyperglycemia seems to target the pituitary gonadotropes directly, and the likely extensive epigenetic changes are sensed acutely by Fshb. This scenario would explain clinical findings in which, even after restoration of optimal blood glucose levels, fertility often remains adversely affected. However, the relative accessibility of the pituitary provides a possible target for treatment, particularly crucial in the young in which hyperglycemia is increasingly common and fertility most relevant.-Feldman, A., Saleh, A., Pnueli, L., Qiao, S., Shlomi, T., Boehm, U., Melamed, P. Sensitivity of pituitary gonadotropes to hyperglycemia leads to epigenetic aberrations and reduced follicle-stimulating hormone levels.

GLUT1-mediated glycolysis supports GnRH-induced secretion of luteinizing hormone from female gonadotropes

“…5 B) and LβT2 cells, we performed expression profiling of Slc2a 1–10, and 12 mRNA and demonstrate that like LβT2 cells, Slc2a1 is the most highly expressed glucose transporter in primary gonadotropes in female mice (Fig. 6 D and 13 ). Importantly, we found that primary gonadotropes exhibit the same Slc2a expression profile as LβT2 cells, though at a higher level.…”

“…Our data in the LβT2 cell line provide evidence that gonadotropes sense glucose and can integrate this information to alter hormone production. Although primary gonadotropes are glucose responsive 13 , to date, no functional protein or metabolic assays have been performed on primary gonadotropes to verify glucose sensing. To answer the question of whether primary gonadotropes respond to GnRH by inducing glycolysis, we devised a protocol to obtain and culture purified primary gonadotropes, a prerequisite for XF analysis.…”

“…Conversely, glucose infusions in castrated male sheep that result in a fourfold increase in plasma glucose concentration increased both LH pulse amplitude and frequency 12 . In vitro , primary mouse gonadotropes are responsive to glucose availability and express high levels of glucose transporter 1 mRNA (GLUT1, encoded by the Slc2a1 gene) 13 . GLUT1 protein and glucose uptake are both increased in LβT2 cells, a gonadotropic cell line, in response to chronic GnRH stimulation in vitro , and this coincides with established effects of GnRH such as increased LH secretion 14 .…”

“…GLUT8 is linked to reproductive regulation via its expression in the testis and blastocysts and may be regulated by insulin 16 – 18 . Primary gonadotropes predominantly express Glut1 mRNA 13 , 14 , and tonic GnRH stimulation increases GLUT1 protein expression in a gonadotrope cell line 14 , indicating that gonadotropes may adjust their metabolism and hormone production in a glucose-dependent manner. Here, we report that regulation of GLUT1 by GnRH and subsequent glycolysis is a process that supports maximal secretion of LH.…”

Early-life environment programs reproductive strategies through epigenetic regulation ofSRD5A1

“…For transcriptome analysis, RNA was extracted from the mice ovaries and purified as above, and sequenced by CEL-seq, using Illumina HiSeq 2500 at the Technion Genome Center (as in 44 ). FastQC was used for quality control and the reads were mapped by TopHat algorithm to mm10 genome assembly.…”