title: Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats.
abstract: Hypogonadotropism is a common feature of uncontrolled diabetes, for which the ultimate mechanism remains to be elucidated. Kisspeptins, ligands of G protein-coupled receptor 54 (GPR54) encoded by the KiSS-1 gene, have recently emerged as major gatekeepers of the gonadotropic axis. Alteration in the hypothalamic KiSS-1 system has been reported in adverse metabolic conditions linked to suppressed gonadotropins, such as undernutrition. However, its potential contribution to defective gonadotropin secretion in diabetes has not been evaluated. We report herein analyses of luteinizing hormone (LH) responses to kisspeptin and hypothalamic expression of the KiSS-1 gene in streptozotocin (STZ)-induced diabetic male rats. In addition, functional studies involving kisspeptin replacement or continuous administration of leptin and insulin to diabetic male rats are presented. Kisspeptin administration evoked robust LH and testosterone bursts and enhanced postgonadectomy LH concentrations, despite prevailing attenuation of gonadotropic axis in diabetic animals. In addition, hypothalamic KiSS-1 mRNA levels were unambiguously decreased in diabetic male rats, and the postorchidectomy rise in KiSS-1 mRNA was severely blunted. Repeated administration of kisspeptin to diabetic rats evoked persistent LH and testosterone responses and partially rescued prostate and testis weights. In addition, central infusion of leptin, but not insulin, was sufficient to normalize hypothalamic KiSS-1 mRNA levels, as well as LH and testosterone concentrations. In summary, we provide evidence for altered expression of the hypothalamic KiSS-1 system in a model of uncontrolled diabetes. This observation, together with the ability of exogenous kisspeptin to rescue defective LH responses in diabetic rats, unravel the physiopathological implication, and potential therapeutic intervention, of the KiSS-1 system in altered gonadotropin secretion of type 1 diabetes.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Faculty of Medicine, University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Castellano
authors.forename: Victor M
authors.initials: VM
authors.lastname: Navarro
authors.forename: Rafael
authors.initials: R
authors.lastname: Fernández-Fernández
authors.forename: Juan
authors.initials: J
authors.lastname: Roa
authors.forename: Eva
authors.initials: E
authors.lastname: Vigo
authors.forename: Rafael
authors.initials: R
authors.lastname: Pineda
authors.forename: Carlos
authors.initials: C
authors.lastname: Dieguez
authors.forename: Enrique
authors.initials: E
authors.lastname: Aguilar
authors.forename: Leonor
authors.initials: L
authors.lastname: Pinilla
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D059648:Kisspeptins; D020738:Leptin / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D009919:Orchiectomy; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013739:Testosterone / Q000378:metabolism
chemical_list: D007328:Insulin; C106628:KISS1 protein, human; C491406:Kiss1 protein, rat; D059648:Kisspeptins; D020738:Leptin; D009842:Oligopeptides; D011506:Proteins; D013739:Testosterone; D007986:Luteinizing Hormone