Metabolic regulation of female puberty via hypothalamic AMPK–kisspeptin signaling

Oct 24, 2018Proceedings of the National Academy of Sciences of the United States of America

How energy use in the brain’s hormone system may control puberty in girls

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Abstract

Central AMPK signaling is associated with the regulation of puberty onset in conditions of energy insufficiency.

Hypothalamic AMPK levels increase in response to pubertal subnutrition, which delays puberty.
Activation of brain AMPK in immature female rats significantly defers puberty onset.
Overexpression of an active form of AMPK in the hypothalamic arcuate nucleus partially delays puberty and lowers luteinizing hormone levels.
Kiss1 neurons in the arcuate nucleus express pAMPK, and AMPK activation decreases their expression.
The removal of the AMPKα1 subunit in Kiss1 cells prevents the puberty delay linked to chronic subnutrition.

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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,, 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 ARCexpression. 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. Kiss1Kiss1

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Metabolic regulation of female puberty via hypothalamic AMPK–kisspeptin signaling

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