Endocrine Abstracts

The connection between metabolic state and fertility is well-recognized, and the hypothalamus clearly plays a central role in translating metabolic signals into altered GnRH release which affects the reproductive axis. We hypothesized that the gonadotropes might also directly impart some of the effects of hyperglycemia on reproductive function. Gonadotropes were shown to express predominantly the insulin-independent Glut-1 transporter, and their incubation in high glucose increases expression of the glucose responsive Txnip gene while altering levels of various glucose metabolites. The drop in NAD+ and increase in α-ketoglutarate affect the activity of Sirtuin histone deacetylases, JmjD histone demethylases and Tet DNA hydroxymethylases/demethylases, all of which use these metabolites as cofactors. Accordingly, gonadotropes in high glucose showed elevated histone acetylation and H3K4 trimethylation, reduced DNA methylation and increased hydroxymethylation, all of which are associated with elevated gene expression. Transcriptome analysis revealed that expression of many genes increased after incubation in high glucose. Notably however, Fshb expression was repressed in high glucose conditions, both in cultured cells and in two hyperglycemic mouse models in vivo. In one of these, circulating FSH levels were also significantly reduced. Increased expression and secretion of inhibin appears partly responsible for this repressive effect on Fshb. Although return of cells to normal glucose restored expression of some of the genes, Fshb levels remained low and the affected chromatin modification were not reversed. Our findings suggest that hyperglycemia aberrantly affects the gonadotrope epigenome with potentially long-term effects on gene expression and thus also reproductive function.