SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression

M. J. Vazquez, C. A. Toro, J. M. Castellano, F. Ruiz-Pino, J. Roa, D. Beiroa, V. Heras, I. Velasco, C. Dieguez, L. Pinilla, F. Gaytan, R. Nogueiras, M. A. Bosch, Oline Ronnekleiv, Alejandro Lomniczi, Sergio Ojeda, M. Tena-Sempere

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article number4194
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Sirtuin 1
obesity
cues
nutrients
Nutrients
Puberty
Obesity
time measurement
nutrition
Food
perturbation
chromatin
neurons
genes
switches
Epigenomics
activation
Cues
molecules
Epigenetic Repression

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Vazquez, M. J., Toro, C. A., Castellano, J. M., Ruiz-Pino, F., Roa, J., Beiroa, D., ... Tena-Sempere, M. (2018). SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. Nature Communications, 9(1), [4194]. https://doi.org/10.1038/s41467-018-06459-9

SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. / Vazquez, M. J.; Toro, C. A.; Castellano, J. M.; Ruiz-Pino, F.; Roa, J.; Beiroa, D.; Heras, V.; Velasco, I.; Dieguez, C.; Pinilla, L.; Gaytan, F.; Nogueiras, R.; Bosch, M. A.; Ronnekleiv, Oline; Lomniczi, Alejandro; Ojeda, Sergio; Tena-Sempere, M.

In: Nature Communications, Vol. 9, No. 1, 4194, 01.12.2018.

Research output: Contribution to journalArticle

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, O, Lomniczi, A, Ojeda, S & Tena-Sempere, M 2018, 'SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression', Nature Communications, vol. 9, no. 1, 4194. https://doi.org/10.1038/s41467-018-06459-9
Vazquez, M. J. ; Toro, C. A. ; Castellano, J. M. ; Ruiz-Pino, F. ; Roa, J. ; Beiroa, D. ; Heras, V. ; Velasco, I. ; Dieguez, C. ; Pinilla, L. ; Gaytan, F. ; Nogueiras, R. ; Bosch, M. A. ; Ronnekleiv, Oline ; Lomniczi, Alejandro ; Ojeda, Sergio ; Tena-Sempere, M. / SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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