A1 Refereed original research article in a scientific journal
SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression
Authors: Vazquez MJ, Toro CA, Castellano JM, Ruiz-Pino F, Roa J, Beiroa D, Heras V, Velasco I, Dieguez C, Pinilla L, Gaytan F, Nogueiras R, Bosch MA, Ronnekleiv OK, Lomniczi A, Ojeda SR, Tena-Sempere M
Publisher: NATURE PUBLISHING GROUP
Publication year: 2018
Journal: Nature Communications
Journal name in source: NATURE COMMUNICATIONS
Journal acronym: NAT COMMUN
Article number: ARTN 4194
Volume: 9
First page : 1
Last page: 15
Number of pages: 15
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-018-06459-9
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/36520403
Puberty is regulated by epigenetic mechanisms and is highly sensitive to metabolic and nutritional cues. However, the epigenetic pathways mediating the effects of nutrition and obesity on pubertal timing are unknown. Here, we identify Sirtuin 1 (SIRT1), a fuel-sensing deacetylase, as a molecule that restrains female puberty via epigenetic repression of the puberty-activating gene, Kiss1. SIRT1 is expressed in hypothalamic Kiss1 neurons and suppresses Kiss1 expression. SIRT1 interacts with the Polycomb silencing complex to decrease Kiss1 promoter activity. As puberty approaches, SIRT1 is evicted from the Kiss1 promoter facilitating a repressive-to-permissive switch in chromatin landscape. Early-onset overnutrition accelerates these changes, enhances Kiss1 expression and advances puberty. In contrast, undernutrition raises SIRT1 levels, protracts Kiss1 repression and delays puberty. This delay is mimicked by central pharmacological activation of SIRT1 or SIRT1 overexpression, achieved via transgenesis or virogenetic targeting to the ARC. Our results identify SIRT1-mediated inhibition of Kiss1 as key epigenetic mechanism by which nutritional cues and obesity influence mammalian puberty.
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