Abstract
The mechanisms mediating suppression of reproduction in response to decreased nutrient availability remain undefined, with studies suggesting regulation occurs within the hypothalamus, pituitary, or gonads. By manipulating glucose utilization and GLUT1 expression in a pituitary gonadotrope cell model and in primary gonadotropes, we show GLUT1-dependent stimulation of glycolysis, but not mitochondrial respiration, by the reproductive neuropeptide GnRH. GnRH stimulation increases gonadotrope GLUT1 expression and translocation to the extracellular membrane. Maximal secretion of the gonadotropin Luteinizing Hormone is supported by GLUT1 expression and activity, and GnRH-induced glycolysis is recapitulated in primary gonadotropes. GLUT1 expression increases in vivo during the GnRH-induced ovulatory LH surge and correlates with GnRHR. We conclude that the gonadotropes of the anterior pituitary sense glucose availability and integrate this status with input from the hypothalamus via GnRH receptor signaling to regulate reproductive hormone synthesis and secretion.
Highlights
The mechanisms mediating suppression of reproduction in response to decreased nutrient availability remain undefined, with studies suggesting regulation occurs within the hypothalamus, pituitary, or gonads
There is evidence that a global metabolic response in gonadotropes is associated with gonadotropin-releasing hormone (GnRH) stimulation and luteinizing hormone (LH) secretion. mRNA-seq was performed on sorted pituitaries from female mice in proestrus and diestrus[19]
LβT2 cells are an excellent model for deciphering mechanisms of GnRH action that can be subsequently validated in vivo, including regulation of LH and follicle-stimulating hormone (FSH) secretion by GnRH pulse frequency and a mplitude[19,24,25,26,27]
Summary
The mechanisms mediating suppression of reproduction in response to decreased nutrient availability remain undefined, with studies suggesting regulation occurs within the hypothalamus, pituitary, or gonads. We conclude that the gonadotropes of the anterior pituitary sense glucose availability and integrate this status with input from the hypothalamus via GnRH receptor signaling to regulate reproductive hormone synthesis and secretion. Intermittent fasting in female rats, which results in reduced blood glucose levels, suppresses luteinizing hormone (LH) and disrupts estrous c ycles[4] These studies indicate that low nutrient availability is sensed by the HPG-axis and results in reduced LH secretion. 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 is increased in gonadotropes during puberty in mice[31] Together, these studies suggest that glucose transport is associated with LH secretion and that gonadotropes may sense glucose and adapt gonadotropin secretion in response to energy availability. Using a novel fluorescence activated cell sorting (FACS) approach to culture wild-type mouse gonadotropes, we demonstrate that this process occurs directly in primary pituitary cells and is correlated with GnRHR expression
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