ESPEYB18 7. Puberty Basic Science (4 abstracts)
7.10. Central ceramide signaling mediates obesity-induced precocious Puberty
Heras V , Castellano JM , Fernandois D , Velasco I , Rodríguez-Vazquez E , Roa J , Vazquez MJ , Ruiz-Pino F , Rubio M , Pineda R , Torres E , Avendaño MS , Paredes A , Pinilla L , Belsham D , Diéguez C , Gaytán F , Casals N , López M & Tena-Sempere M
Cell Metab. 2020 Dec 1;32(6):951–966.e8. 10.1016/j.cmet.2020.10.001. PMID: 33080217. https://www.sciencedirect.com/science/article/pii/S1550413120305349?via%3Dihub
In brief: This study reveals the critical role of hypothalamic ceramide synthesis in the induction of precocious puberty in obese female rats.
Comment: Recent years have brought evidence on the link between the rising prevalence of child obesity and the advancement of puberty timing, especially in girls (1). Even if recent data indicate a contribution of key regulators such as leptin, ghrelin, kisspeptin or SIRT1, the underlying mechanisms are not yet fully understood. Ceramides are a large family of lipid-signalling molecules with major metabolic roles (2). They act as transmitters for the central actions of leptin and ghrelin (3, 4).
This study aimed to determine whether hypothalamic ceramides play a role in the central control of puberty and contribute to its disruption in obesity. Using a model of early overnutrition, the authors showed that early-onset obesity increased hypothalamic ceramide content and advanced puberty in female rats. Using pharmacological tools, stimulation of ceramide synthesis induced early pubertal onset, while its blockade delayed puberty and prevented kisspeptin activating signals. These effects were sexually dimorphic, as no change was observed in pubertal male rats. This observation is consistent with the stronger association between obesity and early puberty in girls than boys. Additionally, the authors reported deregulated ovarian sympathetic tone in early-onset obesity. This phenomenon appeared to involve the paraventricular nucleus (PVN), as early-onset obesity enhanced PVN expression of SPTLC1, a key enzyme for ceramide synthesis, and advanced the maturation of the ovarian noradrenergic system. The blockade of ceramide synthesis in the PVN reversed obesity-induced puberty. In conclusion, this study describes a new pathway explaining precocious puberty in conditions of obesity in female. It includes de novo ceramide synthesis in the PVN and sympathetic ovarian innervation.
Reference: 1. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? Lancet Child Adolesc Health. 2019 Jan;3(1):44-54. doi: 10.1016/S2352-4642(18)30306-7. Epub 2018 Nov 14. PMID: 30446301.2. Chaurasia, B., and Summers, S.A. (2015). Ceramides - lipotoxic inducers of metabolic disorders. Trends Endocrinol. Metab. 26, 538–550.3. Ramı´rez, S., Martins, L., Jacas, J., Carrasco, P., Pozo, M., Clotet, J., Serra, D., Hegardt, F.G., Diéguez, C., López, M., and Casals, N. (2013). Hypothalamic ceramide levels regulated by CPT1C mediate the orexigenic effect of ghrelin. Diabetes 62, 2329–2337.4. Gao, S., Zhu, G., Gao, X., Wu, D., Carrasco, P., Casals, N., Hegardt, F.G., Moran, T.H., and Lopaschuk, G.D. (2011). Important roles of brain-specific carnitine palmitoyltransferase and ceramide metabolism in leptin hypothalamic control of feeding. Proc. Natl. Acad. Sci. USA 108, 9691–9696.
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ESPE Yearbook of Paediatric Endocrinology
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