ECE2018 Oral Communications Look who is controlling your gonads! (5 abstracts)
Novel role of central ceramide signaling in mediating obesity-induced precocious puberty
Violeta Heras 1 , Juan Manuel Castellano 1 , Daniela Fernandois 2 , Inmaculada Velasco 1 , Juan Roa 1 , María J. Vazquez 1, , Francisco Ruiz-Pino 1 , Rafael Pineda 1 , Encarnación Torres 1 , María Soledad Avendaño 1 , Francisco Gaytán 1, , Leonor Pinilla 1, , Miguel López 4 , Nuria Casals 5 & Manuel Tena-Sempere 1,
1Department of Cell Biology, Physiology and Immunology, University of Córdoba and Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, 14004 Cordoba, Spain; 2Laboratory of Neurobiochemistry, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, University of Chile, Santiago de Chile, Chile; 3CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 14004 Cordoba, Spain; 4Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; 5Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallés, Spain.
Childhood obesity has become a major health problem, which is coupled to different adverse outcomes and diseases. The escalating prevalence of child obesity parallels that of alterations in pubertal timing, also linked to higher disease burden later on life. Yet, the mechanisms underlying for this association remain unfolded. Ceramides, ubiquitous signaling molecules involved in numerous biological processes, have emerged as mediators of metabolic disorders and transmitters for the central actions of key hormonal regulators of metabolism and puberty. We address herein the potential contribution of central ceramide signaling to the control of puberty and its alterations due to early-onset obesity. Postnatal overnutrition of female rats, which markedly elevated body weight and advanced puberty, was associated to consistent increases of different ceramide species in the hypothalamus. Pharmacological activation of central ceramide signaling in conditions of normal nutrition partially mimicked the advancement of puberty onset caused by obesity, without changes in body weight, while its persistent blockade with the inhibitor, myriocin, delayed puberty, both in lean and obese females. Myriocin prevented also the permissive effects of the puberty-activating signal, kisspeptin, on puberty onset, but failed to alter basal gonadotropin levels, hypothalamic Kiss1 expression or kisspeptin-induced GnRH/LH release during the peripubertal period, therefore suggesting alternative pathways. We identify here a circuit, involving the paraventricular nucleus (PVN) and ovarian sympathetic innervation, as putative conduit for such novel kisspeptin-ceramide pathway, as (i) PVN received abundant kisspeptin fibers in pubertal rats; (ii) precocious puberty linked to early-onset obesity was associated with advanced maturation of the sympathetic tone at the ovary; and (iii) virogenetic interference of ceramide synthesis at the PVN, by silencing of serine palmitoyltransferase long chain base subunit 1 (SPTLC1), partially normalized ovarian sympathetic activity and the timing of puberty onset in obese rats. All in all, our data are the first to unveil a role of central ceramide signaling in the control of pubertal timing and its alterations due to early-onset obesity. Our results disclose an alternative pathway, linking PVN ceramide synthesis and sympathetic ovarian innervation, as key for such obesity-induced precocious puberty, which may help to define better strategies for the management of pubertal disorders associated to metabolic disease.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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