Puberty is under the precise control of sophisticated regulatory networks, which integrate a large number of endogenous and environmental signals, including metabolic and nutritional cues. Thus, puberty onset is tightly bound to the state of body energy reserves, and deregulation of energy/metabolic homeostasis is often associated with alterations in the timing of puberty. However, despite recent progress in the field, our knowledge of the specific signals and central molecular mechanisms whereby puberty onset is modulated by metabolic factors remains fragmentary and incomplete.
Compelling evidence, gathered over the last fifteen years, supports an essential role of hypothalamic neurons producing kisspeptins, encoded by Kiss1, in the neuroendocrine control of puberty. Kiss1 neurons are major components of the hypothalamic GnRH pulse generator, whose full activation is mandatory pubertal onset. Kiss1 neurons seemingly participate in transmitting the regulatory actions of metabolic cues on pubertal maturation. However, the modulatory influence of metabolic signals (e.g., leptin) on Kiss1 neurons might be predominantly indirect and likely involves also the interaction with other transmitters and neuronal populations.
We will review herein recent work of our group addressing the molecular mechanisms whereby Kiss1 neurons are modulated by metabolic signals, thereby contributing to the nutritional control of puberty. Specially, the roles of the energy/ metabolic sensors, AMP-activated protein kinase (AMPK) and SIRT-1, in the metabolic control of Kiss1 neurons will be discussed. Our data demonstrate that AMPK and SIRT1 operate as central regulatory hubs within Kiss1 neurons to transduce the effects of both sub-nutrition and obesity on puberty onset, by repressing or activating Kiss1 expression. These findings are posed of translational interest, as perturbations of these molecular pathways may contribute to the alterations of pubertal timing linked to conditions of metabolic stress in humans, ranging from malnutrition or obesity, and might become druggable targets for better management of pubertal disorders.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology