RT Journal Article
T1 SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression.
A1 Vazquez, M J
A1 Toro, C A
A1 Castellano, J M
A1 Ruiz-Pino, F
A1 Roa, J
A1 Beiroa, D
A1 Heras, V
A1 Velasco, I
A1 Dieguez, C
A1 Pinilla, L
A1 Gaytan, F
A1 Nogueiras, R
A1 Bosch, M A
A1 Rønnekleiv, O K
A1 Lomniczi, A
A1 Ojeda, S R
A1 Tena-Sempere, M
K1 Nutritional Physiological Phenomena
K1 Nutritional Status
K1 Obesity
K1 Polycomb Repressive Complex 2
K1 Promoter Regions, Genetic
K1 Rats, Wistar
K1 Sexual Maturation
AB 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.
PB Nature Publishing Group
YR 2018
FD 2018-09-04
LK http://hdl.handle.net/10668/13058
UL http://hdl.handle.net/10668/13058
LA en
NO Vazquez MJ, Toro CA, Castellano JM, Ruiz-Pino F, Roa J, Beiroa D, et al. SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. Nat Commun. 2018 Oct 10;9(1):4194
NO This work was supported by grants BFU2011-025021, BFU2014-57581-P, and BFU2017-83934-P (Ministerio de Economía y Competitividad, Spain; co-funded with EU funds from FEDER Program) to M.T.-S.; project PIE-00005 (Flexi-Met, Instituto de Salud Carlos III, Ministerio de Sanidad, Spain) to M.T.-S.; Projects P08-CVI-03788 and P12-FQM-01943 (Junta de Andalucía, Spain) to M.T.-S.; EU research contract DEER FP7-ENV-2007-1 toM.T.-S.; and the National Institute of Health (1R01HD084542) to S.R.O. and A.L., (RO1DK068098) to O.K.R. and 8P51OD011092 for the operation of the Oregon National Primate Research Center. This project has received funding from the EU Horizon 2020 Program, under the Marie Sklodowska-Curie grant agreement No. GAP-2014-655232. C. A.T. was supported by NIH Training grant T32-HD007133 and NRSA grant F32-HD86904, and J.M.C. was funded by SAF2014-56995-JIN (Ministerio de Economía y Competitividad, Spain). CIBER Fisiopatología de la Obesidad y Nutrición is an initiative of Instituto de Salud Carlos III. Senior authors are indebted to M. Serrano (IRB, Barcelona, Spain) for provision of relevant mouse lines, essential for conduction of some ofthe experiments of this study.
DS RISalud
RD Apr 6, 2025