ESPEYB16 7. Puberty Basic Science (3 abstracts)
7.2. SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression
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 , Rønnekleiv OK , Lomniczi A , Ojeda SR & Tena-Sempere M
To read the full abstract: Nat Commun. 2018 Oct 10;9(1):4194.
This study identifies Sirtuin 1 (SIRT1), a fuel-sensing deacetylase, as a molecule that restrains female puberty via epigenetic repression of the puberty-activating gene, Kiss1 in rats.
The last few years have brought evidence regarding the epigenetic control of the onset of puberty. It is now clearly established that a switch from epigenetic repression to activation within kisspeptin neurons in the arcuate nucleus is a core mechanism underlying the initiation of female puberty. However, little is known about the pathways conveying epigenetic information from different stimuli, such as nutrition, circadian activity and environmental toxins/endocrine disruptors to the hypothalamic cells controlling the timing of puberty. The KNDy neurons produce Kisspeptin, NKB (neurokinin B) and Dynorphin and drive the changes in GnRH secretion that set-in motion the endocrine manifestations of puberty (1). They serve as nodal portals for nutritional cues to influence reproductive development and are subjected to a repressive epigenetic control, imposed by the Polycomb (PcG) silencing complex that prevents the premature activation of puberty (2).
Sirtuin 1 (SIRT1) is a deacetylase, highly expressed in the brain and acting on histones and other cellular targets. It senses cell energy and modulates life/health span (3, 4). These authors show that SIRT1 is expressed in hypothalamic Kiss1 neurons and suppresses Kiss1 expression, via interaction with the Polycomb silencing complex. As puberty approaches, SIRT1 is evicted from the Kiss1 promoter facilitating a switch in local chromatin configuration from repressive to permissive. These changes are accelerated by early-onset obesity, which induces precocious puberty, and are postponed by undernutrition, which delays puberty. The causal link between these changes and obesity remains to be explored. This study illustrates the potential pathophysiological role that SIRT1 may play in eliciting pubertal perturbations associated with early-onset obesity and undernutrition.
References: 1. Lehman, MN, Coolen LM, Goodman RL. 2010. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 151: 3479–3489.
2. Lomniczi A, Loche A, Castellano JM, Ronnekleiv OK, Bosch M, Kaidar G, Knoll JG, Wright H, Pfeifer GP, Ojeda SR. 2013 Epigenetic control of female puberty. Nat. Neurosci. 16 (3):281–9.
3. Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, Horvath TL, Sinclair DA, Pfluger PT, Tschöp MH. 2012 Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol. Rev. 92: 1479–1514.
4. Giblin, W, Skinner ME, Lombard DB. 2014. Sirtuins: guardians of mammalian healthspan. Trends Genet. 30: 271–286.
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ESPE Yearbook of Paediatric Endocrinology
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