Insulin Regulation of GnRH Gene Expression through MAP Kinase Signaling Pathways

Kim, Helen H.; DiVall, Sara A.; Deneau, Robyn M.; Wolfe, Andrew

doi:10.1016/j.mce.2005.07.002

Cited by 78Hypothalamic control of reproductive hormonesReproductive Biology and FertilityGrowth Hormone and Insulin-like Growth Factors

Insulin Regulation of GnRH Gene Expression through MAP Kinase Signaling Pathways

Kim, Helen H., DiVall, Sara A., Deneau, Robyn M., Wolfe, Andrew·2005·Molecular and Cellular Endocrinology

DOI 10.1016/j.mce.2005.07.002

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Abstract

In mammals, reproduction is acutely regulated by metabolic status. Insulin is an important nutritional signal from the periphery that may regulate the reproductive axis. To determine whether insulin acts directly on the GnRH neuron, we performed studies in mouse-derived GnRH-expressing cell lines. Both insulin receptor protein and mRNA were detected in these cells. A saturation radioligand binding assay revealed high affinity, low capacity binding sites for insulin in GnRH neurons. Insulin also stimulated GnRH promoter activity in GnRH neurons. This effect was blocked by pretreatment with the MEK inhibitor, PD98059, indicating a role for MAP kinase signaling. In transient transfection studies, insulin treatment stimulated expression of a 1250 bp mouse GnRH gene promoter fragment four-fold when compared to promoter activity in untreated cells. In contrast, insulin did not stimulate activity of a 587 bp fragment of the mGnRH gene promoter, indicating that the promoter elements mediating insulin stimulation of the GnRH promoter are located between -1250 and -587 bp. Our studies suggest that insulin may regulate reproductive function by direct effects on the GnRH neurons and specifically by stimulating GnRH gene expression.

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Insulin affects the hypothalamic-pituitary system by increasing the frequency and amplitude of GnRH release pulses and, in consequence, LH release, which stimulates ovarian cells to androgen synthesis.
“Moreover, insulin affects the hypothalamic-pituitary system. Through MAPK and increased gonadotropin-releasing hormone (GnRH) gene expression, it increases the frequency and amplitude of GnRH release pulses and, in consequence, LH release, which stimulates ovarian cells to androgen synthesis [64].”
From The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome (2022) · cites this paper as [64]

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Authors: Kim, H. H., DiVall, S. A., Deneau, R. M., & Wolfe, A.
Affiliations: University of Chicago (US)
Corresponding author: Wolfe, Andrew
ORCID: Kim, Helen H.
DiVall, Sara A.
Wolfe, Andrew
Venue: Molecular and Cellular Endocrinology
Publisher: Elsevier BV
Published: 2005-10
Volume: 242
Issue: 1-2
Pages: 42-49
ISSN: 0303-7207 (ISSN-L)
DOI: 10.1016/j.mce.2005.07.002
OpenAlex: W2045920950
Cited by: 78
References: 63
Citations by year: 2026: 4 · 2025: 9 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 10 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 2 · 2014: 7 · 2013: 6 · 2012: 2
FWCI: 1.75
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Molecular and Cellular Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD044608)
Topics: Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords: insulin, gonadotropin-releasing hormone, GnRH gene expression, MAPK signaling, MEK, insulin receptor, GnRH neurons, reproductive axis
MeSH terms: Animals, Binding Sites, Cell Line, Cloning, Molecular, Flavonoids, Gene Expression Regulation, Insulin, Gonadotropin-Releasing Hormone, Neurons, Promoter Regions, Genetic, Receptor, Insulin, RNA, Messenger, Transfection, Genes, Reporter, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, Mice

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Insulin Regulation of GnRH Gene Expression through MAP Kinase Signaling Pathways

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