Glucose responsiveness in a novel adult-derived GnRH cell line, mHypoA-GnRH/GFP: Involvement of AMP-activated protein kinase

McFadden, Sean A.; Menchella, Jonathan A.; Chalmers, J. P.; Centeno, Maria-Luisa; Belsham, Denise D.

doi:10.1016/j.mce.2013.06.035

Cited by 21 publications

(13 citation statements)

References 64 publications

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“…Adenosine-monophosphate-activated protein kinase (AMPK) is a sensor of energy status that maintains cellular energy levels in response to changes in nutrient availability, exercise or stress stimuli (18–21). Disruption of this balance is associated with a number of diseases, including diabetes and cancer (22,23).…”

Section: Introductionmentioning

confidence: 99%

AMPK regulates histone H2B O-GlcNAcylation

Yang

et al. 2014

Nucleic Acids Research

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Histone H2B O-GlcNAcylation is an important post-translational modification of chromatin during gene transcription. However, how this epigenetic modification is regulated remains unclear. Here we found that the energy-sensing adenosine-monophosphate-activated protein kinase (AMPK) could suppress histone H2B O-GlcNAcylation. AMPK directly phosphorylates O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT). Although this phosphorylation does not regulate the enzymatic activity of OGT, it inhibits OGT–chromatin association, histone O-GlcNAcylation and gene transcription. Conversely, OGT also O-GlcNAcylates AMPK and positively regulates AMPK activity, creating a feedback loop. Taken together, these results reveal a crosstalk between the LKB1-AMPK and the hexosamine biosynthesis (HBP)-OGT pathways, which coordinate together for the sensing of nutrient state and regulation of gene transcription.

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Section: Introductionmentioning

confidence: 99%

AMPK regulates histone H2B O-GlcNAcylation

Yang

et al. 2014

Nucleic Acids Research

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“…Recent evidences in the mouse GT1-7 clonal GnRH cell line have implicated this GnRH neuronal cell line as direct sensor of glucose, further suggesting that GnRH neurons may sense changes in extracellular glucose directly [29, 30] and that this glucosensing is modulated by gonadal steroids [29, 31]. However, the majority of existing evidence for glucose regulation of GnRH neuron activity is derived from studies of experimental glucoprivation, showing that GnRH neurons are sensitive to changes in glucose concentrations within the physiological range (up to 5 mM), with low doses (<0.5 mM) being able to downregulate GnRH release [29, 31, 32]. In this study, we have tested the effects of exposing FNC-B4 cells to extremely high glucose concentrations (22 and 40 mM), in order to mimic pathological conditions, such as uncontrolled diabetic hyperglycemia, when brain glucose levels more likely exceed 5 mM.…”

Section: Discussionmentioning

confidence: 99%

Negative Effects of High Glucose Exposure in Human Gonadotropin-Releasing Hormone Neurons

Morelli

Comeglio

Sarchielli

et al. 2013

International Journal of Endocrinology

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Metabolic disorders are often associated with male hypogonadotropic hypogonadism, suggesting that hypothalamic defects involving GnRH neurons may impair the reproductive function. Among metabolic factors hyperglycemia has been implicated in the control of the reproductive axis at central level, both in humans and in animal models. To date, little is known about the direct effects of pathological high glucose concentrations on human GnRH neurons. In this study, we investigated the high glucose effects in the human GnRH-secreting FNC-B4 cells. Gene expression profiling by qRT-PCR, confirmed that FNC-B4 cells express GnRH and several genes relevant for GnRH neuron function (KISS1R, KISS1, sex steroid and leptin receptors, FGFR1, neuropilin 2, and semaphorins), along with glucose transporters (GLUT1, GLUT3, and GLUT4). High glucose exposure (22 mM; 40 mM) significantly reduced gene and protein expression of GnRH, KISS1R, KISS1, and leptin receptor, as compared to normal glucose (5 mM). Consistent with previous studies, leptin treatment significantly induced GnRH mRNA expression at 5 mM glucose, but not in the presence of high glucose concentrations. In conclusion, our findings demonstrate a deleterious direct contribution of high glucose on human GnRH neurons, thus providing new insights into pathogenic mechanisms linking metabolic disorders to reproductive dysfunctions.

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“…mHypoA‐GnRH/GFP neurones were maintained at 37 °C with 5% CO 2 , as described previously . These neurones have been characterised previously and were shown to synthesise and secrete GnRH in a regulated manner . RFRP‐3 human trifluoroacetate salt (Sigma‐, Oakville, Canada; amino acid sequence Val‐Pro‐Asn‐Leu‐Pro‐Gln‐Arg‐Phe‐NH2) and Kiss‐10 (Phoenix Pharmaceuticals, Burlingame, CA, USA) were dissolved in water to a final concentration of 100 and 10 n m , respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The present study aimed to determine the direct effects of RFRP‐3, kisspeptin and a kisspeptin/RFRP‐3 co‐treatment on hypothalamic GnRH biosynthesis and release. Because of the complex architecture and heterogeneous nature of the hypothalamus, as well as the lack of an adult‐derived, nonclonal GnRH‐secreting cell line, we use a newly established and characterised GnRH neuronal model, the mHypoA‐GnRH/GFP, previously described in our laboratory . We established that mHypoA‐GnRH/GFP neurones express Gpr147 and Gpr54, and demonstrate c‐Fos activation upon treatment with RFRP‐3 and kisspeptin.…”

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confidence: 99%

Direct Regulation of Gonadotrophin‐Releasing Hormone (GnRH) Transcription By RF‐Amide‐Related Peptide‐3 and Kisspeptin in A Novel GnRH‐Secreting Cell Line, mHypoA‐GnRH/GFP

Gojska

Friedman

Belsham

2014

J Neuroendocrinology

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RF-amide-related peptide-3 [RFRP-3; also often referred to as the mammalian orthologue of the avian gonadotrophin-inhibitory hormone (GnIH)] and kisspeptin have emerged as potent modulators of neuroendocrine function via direct regulation of the reproductive axis in the hypothalamus and pituitary. There are few studies focusing on the direct regulatory effects of RFRP-3 and kisspeptin on gonadotrophin-releasing hormones (GnRH) neurones. We report their effect on GnRH mRNA expression and release in a novel GnRH neuronal cell model, mHypoA-GnRH/GFP, generated from adult-derived GnRH-GFP neurones. The neurones express receptors for both RFRP-3 and kisspeptin, Gpr147 and Gpr54, respectively. Incubation with 100 nm RFRP-3 results in attenuation of GnRH mRNA expression by approximately 60%. Conversely, incubation with 10 nm of Kiss-10 induced GnRH mRNA expression, whereas the combined effect was an overall repression of GnRH mRNA levels. With transcription inhibitors, the repression of GnRH mRNA levels was linked to a transcriptional mechanism but not mRNA stability. No significant changes in GnRH secretion were observed upon RFRP-3 exposure in these neurones. Our findings suggest that the suppressive signalling of RFRP-3 on GnRH transcription may dominate over kisspeptin induction in the mHypoA-GnRH/GFP GnRH neuronal cell model.

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Glucose responsiveness in a novel adult-derived GnRH cell line, mHypoA-GnRH/GFP: Involvement of AMP-activated protein kinase

Cited by 21 publications

References 64 publications

AMPK regulates histone H2B O-GlcNAcylation

AMPK regulates histone H2B O-GlcNAcylation

Negative Effects of High Glucose Exposure in Human Gonadotropin-Releasing Hormone Neurons

Direct Regulation of Gonadotrophin‐Releasing Hormone (GnRH) Transcription By RF‐Amide‐Related Peptide‐3 and Kisspeptin in A Novel GnRH‐Secreting Cell Line, mHypoA‐GnRH/GFP

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