Editors' ChoiceReproductive Biology

The ceramide fast track to puberty

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Science Signaling  22 Dec 2020:
Vol. 13, Issue 663, eabg2177
DOI: 10.1126/scisignal.abg2177

Diet-induced obesity triggers hypothalamic ceramide signaling that leads to precocious puberty in female rats.

At the onset of puberty, the peptide hormone kisspeptin initiates the secretion of gonadotropin-releasing hormone (GnRH), which in turn induces the secretion of gonadotropins that promote sexual maturation. Childhood obesity in girls often accelerates the onset of puberty. Heras et al. found that precocious puberty triggered by diet-induced obesity in female rats was mediated by a circuit involving ceramide signaling in the paraventricular nucleus (PVN) in the hypothalamus and sympathetic ovarian innervation (see also Stamou and Balasubramanian). The authors correlated precocious puberty with increased ceramide concentrations in the hypothalamus. Intracerebroventricular administration of a cell membrane–permeant variant of a ceramide precursor (CER:C6) induced precocious puberty without altering basal gonadotropin amounts or hypothalamic Kiss1 expression. Conversely, puberty was delayed in rats that received myriocin, an inhibitor of SPT (serine palmitoyltransferase), the first enzyme in the de novo synthesis of ceramides. The delay in puberty induced by underfeeding was partially rescued by treatment with exogenous kisspeptin, an effect that was negated by coadministration of myriocin. However, GnRH release in hypothalamic explants was not affected by treatment with either CER:C6 or myriocin. In the PVN, which innervates the ovaries, immunoreactivity for ceramide and the SPT component SPTLC1 increased at the onset of puberty, more so at the onset of precocious puberty. Obesity-induced precocious puberty triggered early sympathetic activation of ovaries by the PVN. This increase in ovarian sympathetic tone was attenuated when central ceramide synthesis was inhibited by intracerebroventricular delivery of myriocin or by delivery of a short hairpin RNA silencing the SPT component SPTLC1 to the PVN. Thus, this pathway may be amenable to pharmacological manipulation to prevent precocious puberty caused by diet-induced obesity, a growing worldwide problem in children.

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