# Post-transcriptional Pathways that Signal Leptin Regulation of Gonadotropes

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2020 · $457,162

## Abstract

PROJECT SUMMARY/ABSTRACT
 The expression of GnRHRs is a critical, rate-limiting step in the reproductive process, however little is
known about the mechanism behind the regulation of translation of GnRHR proteins. Gonadotrope functions
may be limited in times of food deprivation, which is signaled by leptin deficiency, however there is a
fundamental gap in understanding how leptin regulates gonadotropes. Leptin's importance to gonadotropes is
highlighted by the infertile mouse model in which all isoforms of leptin receptors (LEPR) on gonadotropes are
ablated, and the fact that the mutant gonadotropes have severely reduced GnRHR protein, but not mRNA
levels. These findings provide important clues as to how leptin links fertility to metabolic status, however the
molecular mechanisms underlying leptin control of gonadotropes are unknown. Our long-term goal is to fill
this knowledge gap by identifying underlying mechanisms behind the infertility in the gonadotrope Lepr-null
mutant mice. The central hypothesis to be tested is that loss of leptin signaling in gonadotropes
prevents the normal diestrous upregulation of GnRH receptors causing a blunted or absent LH
surge and infertility. A secondary hypothesis that leptin acts through posttranscriptional
mechanisms to optimize gonadotrope function. The proposed studies will focus on three specific aims.
Specific Aim 1 will determine if loss of leptin signaling in gonadotropes reduces fertility through prevention of
the diestrous upregulation of GnRHR protein levels. These studies will ascertain if the Lepr-null
gonadotropes are held in persistent diestrus because of low GnRHR proteins and if the normal surge in serum
gonadotropins is absent. The efficacy of exogenous GnRH in the rescue of GnRHR levels in mutants and
restoration of cyclicity and fertility will be tested. Specific Aim 2 studies will determine if leptin signaling to
mRNA translational control mechanisms is required for gonadotrope function. These studies will globally
assess leptin regulation of gonadotrope mRNA translation and specifically address control of Gnrhr mRNA
translation. Genetic knockdown of identified candidate translational repressors will be used to restore GnRHR
expression in mutant gonadotropes. Specific Aim 3 studies will determine if food deprivation recapitulates the
effect of loss of leptin signaling to gonadotropes, including repression of Gnrhr mRNA translation. These in
vivo studies will test the hypothesis that loss of leptin signaling during food deprivation also prevents diestrous
upregulation of GnRHR. The studies will also determine if the in vitro deletion of identified translational
control mechanisms (e.g. MSI, miRNAs) alleviates the fasting-induced repression of Gnrhr mRNA translation.
Our research is innovative because it investigates the novel concept that leptin may regulate gonadotrope
function at post-transcriptional levels. These findings are significant because clinical protocols used in
infertility tr...

## Key facts

- **NIH application ID:** 9902541
- **Project number:** 5R01HD087057-05
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** GWEN V CHILDS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $457,162
- **Award type:** 5
- **Project period:** 2016-08-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902541

## Citation

> US National Institutes of Health, RePORTER application 9902541, Post-transcriptional Pathways that Signal Leptin Regulation of Gonadotropes (5R01HD087057-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9902541. Licensed CC0.

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