Metabolic regulation of female puberty via hypothalamic AMPK-kisspeptin signaling - UTU Research Portal

A1 Refereed original research article in a scientific journal

Metabolic regulation of female puberty via hypothalamic AMPK-kisspeptin signaling

Authors: Juan Roa, Alexia Barroso, Francisco Ruiz-Pino, Maria Jesus Vázquez, Patricia Seoane-Collazo, Noelia Martínez-Sanchez, David García-Galiano, Tuncay Ilhan, Rafael Pineda, Silvia León, Maria Manfredi-Lozano, Violeta Heras, Matti Poutanen, Juan M. Castellano, Francisco Gaytan, Carlos Diéguez, Leonor Pinilla, Miguel López, Manuel Tena-Sempere

Publisher: NATL ACAD SCIENCES

Publication year: 2018

Journal: Proceedings of the National Academy of Sciences of the United States of America

Journal name in source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Journal acronym: P NATL ACAD SCI USA

Volume: 115

Issue: 45

First page : E10758

Last page: E10767

Number of pages: 10

ISSN: 0027-8424

DOI: https://doi.org/10.1073/pnas.1802053115

Abstract

Conditions of metabolic distress, from malnutrition to obesity, impact, via as yet ill-defined mechanisms, the timing of puberty, whose alterations can hamper later cardiometabolic health and even life expectancy. AMP-activated protein kinase (AMPK), the master cellular energy sensor activated in conditions of energy insufficiency, has a major central role in whole-body energy homeostasis. However, whether brain AMPK metabolically modulates puberty onset remains unknown. We report here that central AMPK interplays with the puberty-activating gene, Kiss1, to control puberty onset. Pubertal subnutrition, which delayed puberty, enhanced hypothalamic pAMPK levels, while activation of brain AMPK in immature female rats substantially deferred puberty. Virogenetic overexpression of a constitutively active form of AMPK, selectively in the hypothalamic arcuate nucleus (ARC), which holds a key population of Kiss1 neurons, partially delayed puberty onset and reduced luteinizing hormone levels. ARC Kiss1 neurons were found to express pAMPK, and activation of AMPK reduced ARC Kiss1 expression. The physiological relevance of this pathway was attested by conditional ablation of the AMPK alpha 1 subunit in Kiss1 cells, which largely prevented the delay in puberty onset caused by chronic subnutrition. Our data demonstrate that hypothalamic AMPK signaling plays a key role in the metabolic control of puberty, acting via a repressive modulation of ARC Kiss1 neurons in conditions of negative energy balance.