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

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.

SUBMITTER: Vazquez MJ

PROVIDER: S-EPMC6179991 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Vazquez M J MJ Toro C A CA Castellano J M JM Ruiz-Pino F F Roa J J Beiroa D D Heras V V Velasco I I Dieguez C C Pinilla L L Gaytan F F Nogueiras R R Bosch M A MA Rønnekleiv O K OK Lomniczi A A Ojeda S R SR Tena-Sempere M M

Nature communications 20181010 1

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 Po ...[more]

PMID: 30305620

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Project description:Autism spectrum disorder (ASD) is characterized by impaired social communication and poor adaptation to change; thus, the onset of puberty may be a pivotal transition. This cross-sectional study measured pubertal timing to examine hypothesized differences for sex (female vs. male) and group (ASD vs. typical development [TD]). Participants included 239 children (137 ASD, 102 TD) between 10 and 13 years. The ASD group included 35 females and 102 males; the TDs included 44 females and 58 males. Pubertal onset measured by genital or pubic stage was investigated with linear regression using main effects of sex and age-by-sex interactions in TD and ASD groups and main effects of diagnosis and diagnosis-by-age interactions in males and females, controlling for body mass index, socioeconomic status, and race. In TD, examination of main effects for genital (penis/breast) stage showed no difference for male and female children (t = 1.33, P = 0.187, rdf = 92); however, there were significant differences in ASD (t = 2.70, P = 0.008, rdf = 121). For diagnosis modeled separately by sex, there was significantly earlier pubertal development in females with ASD (t = 1.97, P = 0.053, rdf = 70, but not males (t = 1.329, P = 0.186, rdf = 143). In addition, analysis of menses revealed females with ASD had significantly earlier onset than TD (t = -2.56, P = 0.018, rdf = 21). Examination of pubic stage revealed expected sex differences for TD (t = 2,674, P = 0.009, rdf = 91) and ASD (t = 3.482, P = 0.001, rdf = 121). Females with ASD evidence advanced pubertal onset relative to ASD males and TD females. Findings underscore the need for enhanced understanding of pubertal development in ASD, as differences may have significant psychological, social, physiological, and developmental consequences. LAY SUMMARY: Children with autism spectrum disorder (ASD) have difficulty with social communication and respond poorly to change, which may include the onset and course of puberty. The study measured the timing of puberty in 239 children (137 ASD and 102 typical development [TD]) between 10 and 13 years based on pubertal stage of genital (breast/penis) and pubic hair development. Females with ASD evidence advanced pubertal onset relative to ASD males and TD females. Findings underscore the need for an enhanced understanding of pubertal development in ASD.

Dataset Information

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

Publications

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

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