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SAT-177 GLUT1-Mediated Glucose Metabolism Is Necessary for GnRH-Induced Gonadotrope Secretion of LH and Is Increased by Androgen
Women with polycystic ovary syndrome (PCOS) have a high prevalence of metabolic comorbidities including dyslipidemia, metabolic syndrome, and type 2 diabetes mellitus. However, the impact of systemic metabolic dysregulation on reproduction is not completely understood. In particular, women with PCOS...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552393/ http://dx.doi.org/10.1210/js.2019-SAT-177 |
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author | Nicholas, Dequina Knight, Vashti Terasaka, Tomohiro in Choi, Jeong Muñoz, Oscar Mellon, Pamela Lawson, Mark |
author_facet | Nicholas, Dequina Knight, Vashti Terasaka, Tomohiro in Choi, Jeong Muñoz, Oscar Mellon, Pamela Lawson, Mark |
author_sort | Nicholas, Dequina |
collection | PubMed |
description | Women with polycystic ovary syndrome (PCOS) have a high prevalence of metabolic comorbidities including dyslipidemia, metabolic syndrome, and type 2 diabetes mellitus. However, the impact of systemic metabolic dysregulation on reproduction is not completely understood. In particular, women with PCOS have elevated androgen as well as elevated blood glucose, insulin, and free fatty acids. These circulating factors can directly interact with gonadotrope cells within the highly vascular pituitary. We therefore postulate that gonadotropes “sense” nutrient availability in their microenvironment and respond to changes by adapting hormone production accordingly. Deciphering how androgens and “nutrient sensing” interact at the level of the gonadotrope may be central to understanding PCOS and improving reproductive outcomes. To understand the impact of metabolic state and nutrient availability on gonadotrope function, we must first determine the cellular metabolic program that supports gonadotrope secretion of luteinizing hormone (LH). Due to the high energy demand of rapid protein synthesis required for LH production, we hypothesized that gonadotropes engage anaerobic glycolysis in response to GnRH stimulation. To test this hypothesis, we measured the cellular energetics of the gonadotrope cell line LβT2 in response to GnRH via extracellular flux analysis. We found that GnRH increases the extracellular acidification rate, a proxy for anaerobic glycolysis. Using microscopy and flow cytometry, we determined that glucose transporter 1 (GLUT1) protein is exclusively expressed in primary gonadotropes in the pituitary and is the most highly expressed GLUT transporter mRNA in both primary gonadotropes and LβT2 cells. Additionally, GLUT1 mediates the GnRH-stimulated increase in glucose uptake. Knockdown of GLUT1 in LβT2 cells diminished GnRH-induced glucose uptake and LH secretion; while overexpression of GLUT1 in LβT2 increased basal LH secretion. Moreover, GnRH-induced LH secretion was proportional to glucose availability. Lastly, an 8-hour treatment with 10nM DHT increased GLUT1 protein expression in LβT2 cells and primary female gonadotropes and increased GnRH-induction of GLUT1 translocation to the cell surface as observed by microscopy. These results implicate glucose uptake through GLUT1 as necessary for gonadotrope secretion of LH and therefore reproductive function. We conclude that GLUT1 expression and translocation may be an important point of regulation by androgen in the HPG-axis and in PCOS. Sources of Research Support: NIH Grant P50 HD012303 awarded to ML and PM; DN is a recipient of the UCSD IRACDA Fellowship (K12 GM068524) and the University of California’s Presidents Postdoctoral Fellowship. |
format | Online Article Text |
id | pubmed-6552393 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-65523932019-06-13 SAT-177 GLUT1-Mediated Glucose Metabolism Is Necessary for GnRH-Induced Gonadotrope Secretion of LH and Is Increased by Androgen Nicholas, Dequina Knight, Vashti Terasaka, Tomohiro in Choi, Jeong Muñoz, Oscar Mellon, Pamela Lawson, Mark J Endocr Soc Diabetes Mellitus and Glucose Metabolism Women with polycystic ovary syndrome (PCOS) have a high prevalence of metabolic comorbidities including dyslipidemia, metabolic syndrome, and type 2 diabetes mellitus. However, the impact of systemic metabolic dysregulation on reproduction is not completely understood. In particular, women with PCOS have elevated androgen as well as elevated blood glucose, insulin, and free fatty acids. These circulating factors can directly interact with gonadotrope cells within the highly vascular pituitary. We therefore postulate that gonadotropes “sense” nutrient availability in their microenvironment and respond to changes by adapting hormone production accordingly. Deciphering how androgens and “nutrient sensing” interact at the level of the gonadotrope may be central to understanding PCOS and improving reproductive outcomes. To understand the impact of metabolic state and nutrient availability on gonadotrope function, we must first determine the cellular metabolic program that supports gonadotrope secretion of luteinizing hormone (LH). Due to the high energy demand of rapid protein synthesis required for LH production, we hypothesized that gonadotropes engage anaerobic glycolysis in response to GnRH stimulation. To test this hypothesis, we measured the cellular energetics of the gonadotrope cell line LβT2 in response to GnRH via extracellular flux analysis. We found that GnRH increases the extracellular acidification rate, a proxy for anaerobic glycolysis. Using microscopy and flow cytometry, we determined that glucose transporter 1 (GLUT1) protein is exclusively expressed in primary gonadotropes in the pituitary and is the most highly expressed GLUT transporter mRNA in both primary gonadotropes and LβT2 cells. Additionally, GLUT1 mediates the GnRH-stimulated increase in glucose uptake. Knockdown of GLUT1 in LβT2 cells diminished GnRH-induced glucose uptake and LH secretion; while overexpression of GLUT1 in LβT2 increased basal LH secretion. Moreover, GnRH-induced LH secretion was proportional to glucose availability. Lastly, an 8-hour treatment with 10nM DHT increased GLUT1 protein expression in LβT2 cells and primary female gonadotropes and increased GnRH-induction of GLUT1 translocation to the cell surface as observed by microscopy. These results implicate glucose uptake through GLUT1 as necessary for gonadotrope secretion of LH and therefore reproductive function. We conclude that GLUT1 expression and translocation may be an important point of regulation by androgen in the HPG-axis and in PCOS. Sources of Research Support: NIH Grant P50 HD012303 awarded to ML and PM; DN is a recipient of the UCSD IRACDA Fellowship (K12 GM068524) and the University of California’s Presidents Postdoctoral Fellowship. Endocrine Society 2019-04-30 /pmc/articles/PMC6552393/ http://dx.doi.org/10.1210/js.2019-SAT-177 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Diabetes Mellitus and Glucose Metabolism Nicholas, Dequina Knight, Vashti Terasaka, Tomohiro in Choi, Jeong Muñoz, Oscar Mellon, Pamela Lawson, Mark SAT-177 GLUT1-Mediated Glucose Metabolism Is Necessary for GnRH-Induced Gonadotrope Secretion of LH and Is Increased by Androgen |
title | SAT-177 GLUT1-Mediated Glucose Metabolism Is Necessary for GnRH-Induced Gonadotrope Secretion of LH and Is Increased by Androgen |
title_full | SAT-177 GLUT1-Mediated Glucose Metabolism Is Necessary for GnRH-Induced Gonadotrope Secretion of LH and Is Increased by Androgen |
title_fullStr | SAT-177 GLUT1-Mediated Glucose Metabolism Is Necessary for GnRH-Induced Gonadotrope Secretion of LH and Is Increased by Androgen |
title_full_unstemmed | SAT-177 GLUT1-Mediated Glucose Metabolism Is Necessary for GnRH-Induced Gonadotrope Secretion of LH and Is Increased by Androgen |
title_short | SAT-177 GLUT1-Mediated Glucose Metabolism Is Necessary for GnRH-Induced Gonadotrope Secretion of LH and Is Increased by Androgen |
title_sort | sat-177 glut1-mediated glucose metabolism is necessary for gnrh-induced gonadotrope secretion of lh and is increased by androgen |
topic | Diabetes Mellitus and Glucose Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552393/ http://dx.doi.org/10.1210/js.2019-SAT-177 |
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