Negative effects of high glucose exposure in human gonadotropin-releasing hormone neurons.
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.
Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
Annamaria
A
Morelli
Section of Sexual Medicine and Andrology, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
Paolo
P
Comeglio
Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
Erica
E
Sarchielli
Section of Sexual Medicine and Andrology, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
Ilaria
I
Cellai
Section of Sexual Medicine and Andrology, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
Linda
L
Vignozzi
Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
Gabriella B
GB
Vannelli
Section of Sexual Medicine and Andrology, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy ; Centro Interuniversitario di Ricerca sulle Basi Molecolari della Malattie della Riproduzione (CIRMAR), 20122 Milan, Italy.
Mario
M
Maggi