Metabolic regulation of female puberty via hypothalamic AMPK–kisspeptin signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 45; pp. E10758 - E10767
• Main Authors: Roa, Juan, Barroso, Alexia, Ruiz-Pino, Francisco, Vázquez, Maria Jesus, Seoane-Collazo, Patricia, Martínez-Sanchez, Noelia, García-Galiano, David, Ilhan, Tuncay, Pineda, Rafael, León, Silvia, Manfredi-Lozano, Maria, Heras, Violeta, Poutanen, Matti, Castellano, Juan M., Gaytan, Francisco, Diéguez, Carlos, Pinilla, Leonor, López, Miguel, Tena-Sempere, Manuel
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 06.11.2018
• Series: PNAS Plus
• Subjects: Ablation; Activation; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Animals, Genetically Modified; Arcuate nucleus; Arcuate Nucleus of Hypothalamus - cytology; Arcuate Nucleus of Hypothalamus - drug effects; Arcuate Nucleus of Hypothalamus - metabolism; Biological Sciences; Brain; Caloric Restriction - adverse effects; Endocrinology and Diabetes; Endokrinologi och diabetes; Energy balance; Estradiol - pharmacology; Female; Gene Expression Regulation, Developmental; Homeostasis; Hypothalamus; Kiss1 protein; Kisspeptins - genetics; Kisspeptins - metabolism; Life expectancy; Life span; Luteinizing hormone; Luteinizing Hormone - blood; Malnutrition; Malnutrition - genetics; Malnutrition - metabolism; Malnutrition - physiopathology; Metabolic disorders; Mice; Mice, Inbred C57BL; Neuromodulation; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; PNAS Plus; Proteins; Puberty; Rats; Rats, Wistar; Ribonucleotides - pharmacology; Sexual Maturation - genetics; Signal Transduction; Signaling; Time Factors; Kiss1; AMPK; energy balance; puberty; undernutrition
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1802053115

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 AMPKα1 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.