Endocrine Abstracts (2013) 32 P680 | DOI: 10.1530/endoabs.32.P680

High glucose induces hypogonadotropic hypogonadism by interfering with GPR54 signaling in the preoptic area of the hypothalamus

Annamaria Morelli1, Linda Vignozzi2, Sarchielli Erica1, Paolo Comeglio2, Sandra Filippi2, Giulia Rastrelli2, Elena Maneschi2, Ilaria Cellai2, Gabriella Barbara Vannelli1 & Mario Maggi2

1Deparment of Experimental and Clinical Medicine, University of Florence, Florence, Italy; 2Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.

The metabolic syndrome (MetS) is a clustering of metabolic and cardiovascular risk factors, having in insulin resistance the key element. In males, MetS is also associated to hypogonadism. We recently found that high fat diet (HFD)-induced MetS rabbits also developed hypogonadotropic hypogonadism, showing a reduced immunopositivity for gonadotropin relasing hormone (GnRH) in the hypothalamus. In this study, we investigated the pathogenetic link between Mets components and the onset of hypogonadism in the MetS animal model. Interestingly, low gonadotropin level significantly correlated with MetS components and elevated glucose and cholesterol levels resulted the major determinants for this association. In agreement, glucose tolerance, evaluated in vivo by oral glucose tolerance test (AUC-OGTT), correlated negatively with gonadotropin level. We identified a positive association between the number of factors of the MetS and GLUT4, a glucose transporter, gene expression. GLUT4 was negatively associated with gonadotropin level and positively with AUC-OGTT and hypothalamic gene expression of inflammatory markers, such as cycloxigenase 2 (COX2) and interleukin-6 (IL-6). Glucose tolerance resulted significantly associated with the mRNA expression of GPR54 in the preoptic area of the hypothalamus and in agreement, the immunopositivity for GPR54 was significantly reduced in the hypothamic sections of HFD rabbits. KiSS1/GPR54 system is a central regulator of GnRH neurons. We therefore studied the effects of high glucose in human fetus-derived GnRH-secreting neuroblasts, the FNCB4 cell line. High glucose exposure (22 and 40 mM) significantly reduced the expression of GnRH, KiSS1 and GPR54. A subset of HFD rabbits was treated with INT-747, able to ameliorate the metabolic profile. This treatment was able to increase GnRH, and to reduce, COX2 and IL-6- gene expression; without preventing HFD-related hypogonadotropic hypogonadism. In conclusion, our results suggest that negative effects of hyperglycemia on hypothalamic function may contribute to testosterone deficiency in MetS.