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Nat Commun. 2018 Oct 10;9(1):4194. doi: 10.1038/s41467-018-06459-9.

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

Vazquez MJ1,2,3,4, Toro CA5, Castellano JM1,2,3,4, Ruiz-Pino F1,2,3,4, Roa J1,2,3,4, Beiroa D6, Heras V1,2,3, Velasco I1,2,3,4, Dieguez C4,6, Pinilla L1,2,3,4, Gaytan F1,2, Nogueiras R4,6, Bosch MA7, Rønnekleiv OK7,8, Lomniczi A9, Ojeda SR8, Tena-Sempere M10,11,12,13,14.

Author information

1
Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), 14004, Cordoba, Spain.
2
Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004, Cordoba, Spain.
3
Hospital Universitario Reina Sofia, 14004, Cordoba, Spain.
4
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004, Cordoba, Spain.
5
Division of Genetics, Oregon National Primate Research Center/Oregon Health and Science University, Beaverton, OR, 97006, USA.
6
Department of Physiology, Faculty of Medicine and CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.
7
Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, 97239, USA.
8
Division of Neuroscience, Oregon National Primate Research Center/Oregon Health and Science University, Beaverton, OR, 97006, USA.
9
Division of Genetics, Oregon National Primate Research Center/Oregon Health and Science University, Beaverton, OR, 97006, USA. lomniczi@ohsu.edu.
10
Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), 14004, Cordoba, Spain. fi1tesem@uco.es.
11
Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004, Cordoba, Spain. fi1tesem@uco.es.
12
Hospital Universitario Reina Sofia, 14004, Cordoba, Spain. fi1tesem@uco.es.
13
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004, Cordoba, Spain. fi1tesem@uco.es.
14
FiDiPro Program, University of Turku, Turku, 20014, Finland. fi1tesem@uco.es.

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.

PMID:
30305620
PMCID:
PMC6179991
DOI:
10.1038/s41467-018-06459-9
[Indexed for MEDLINE]
Free PMC Article

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