ECE2020 Oral Communications Reproductive and Developmental Endocrinology (7 abstracts)
Identification of a novel hypothalamic miRNA/Kisspeptin pathway as pathophysiological mechanism and putative target for management of obesity-induced hypogonadism
Cecilia María Perdices López 1,2,3 , María Soledad Avendaño Herrador 1,2 , María Jesús Vázquez Villar 1,2,3 , Alexia Barroso Romero 1,2 , Francisco Ruiz Pino 1,2,3 , Rosario Morrugares Carmona 1,2 , Alejandro Correa Sáez 1,2 , Marco Antonio Calzado 1,2 , Juan Manuel Castellano Rodríguez 1,2,3 , Ana María Briones Alonso 4 & Manuel Tena-Sempere 1,2,3
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain; 2Cordoba University, Cell Biology, Physiology and Immunology Department, Córdoba, Spain; 3Institute of Health Carlos III (ISCIII), CIBER Fisiopatología de la Obesidad y Nutrición, Madrid, Spain; 4Autonomous University of Madrid , Madrid, Spain
Among its numerous comorbidities, obesity is often linked to central hypogonadism in men, i.e., low circulating levels of gonadotropins and testosterone. While this condition of obesity-induced hypogonadism (OIH) is frequently neglected, it has been suggested to contribute to the metabolic complications of male obesity. However, the mechanisms of OIH, and even its actual role in the metabolic alterations of obesity remain ill defined. Our recent data suggest that OIH is bound to suppression of the hypothalamic Kiss1/kisspeptin system, which would lower gonadotropin levels and, thereby, testosterone in obese males. Yet, the mechanisms for Kiss1 suppression in obesity remains unknown. Our recent findings suggest that microRNAs might operate as putative regulators of Kiss1. Here, we identify a novel miRNA pathway regulating kisspeptin expression, and assess its potential contribution to OIH. Bioinformatic prediction of miRNA regulators of the KISS1 gene were conducted with several algorithms, searching for putative seed regions at the 3’ untranslated region (3’UTR) of KISS1. For selection, miRNA candidate(s) had to meet the following criteria: 1) to be identified in at least two databases; 2) to display evolutionary conservation of its seed regions; and 3) to be sensitive to metabolic regulation, according to previous literature. Based on these criteria, miR-A (anonymized due to ongoing patent protection) was selected as a robust putative modulator of KISS1. Luciferase reporter assays confirmed a repressive interaction of miR-A at the 3’UTR of KISS1. Hypothalamic expression of miR-A was increased in obese male rats displaying OIH. Moreover, in vivo administration of a target-site blocker (TSB), tailored to specifically prevent the repressive interaction of miR-A at the 3’UTR of Kiss1, significantly ameliorated the reproductive and metabolic alterations observed in a rat model of OIH. Thus, while OIH rats showed severe suppression of T and gonadotropin (LH) levels, together with notable metabolic alterations (glucose intolerance, insulin resistance), elevated systolic blood pressure and severe inflammation, TSB administration not only restored T and LH levels, and enhanced hypothalamic kisspeptin, but improved also the metabolic alterations seen in OIH rats, even more effectively than pharmacological treatments with either kisspeptin or T. In sum, we provide herein preclinical evidence for a major role of a central miR-A/kisspeptin pathway in the generation OIH. This pathway might be a suitable target for the management of central hypogonadism linked to obesity, and its major metabolic complications.
Volume 70
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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