Metabolic regulation of female puberty via hypothalamic AMPK–kisspeptin signaling

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 ARCKiss1expression. 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.

Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition

“…These mice, named KAMKO (for Kiss1-specific AMPK knockout), failed to display major alterations in pubertal timing in conditions of feeding ad libitum, but were partially protected against the delay in pubertal maturation caused by chronic undernutrition. Altogether, these studies illustrate the fundamental role of hypothalamic AMPK signaling in the metabolic control of puberty, acting via repressive modulation of ARC Kiss1 neurons in conditions of negative energy balance (Roa et al 2018).…”

“…In this context, recent studies from our group have thoroughly documented a novel neuroendocrine circuit linking conditions of negative energy balance and pubertal timing via the AMPK-Kiss1 pathway (Roa et al 2018). Thus, chronic peripubertal subnutrition, which was associated to the expected delay in the age of vaginal opening, caused a significantly increase of hypothalamic p-AMPK levels in female rats.…”

How treatments with endocrine and metabolic drugs influence pituitary cell function

“…In the same model, overexpression of a constitutively active form of AMPK in the ARC partially delayed puberty onset and decreased LH levels. On the other hand, conditional ablation of the AMPKα1 subunit in the ARC prevented the delay in puberty onset caused by chronic malnutrition (40). These data suggest that hypothalamic AMPK signalling has an important role in mediating the effects of malnutrition on the control of puberty through a repressive AMPK-Kisspeptin pathway.…”

Lin28 gene and mammalian puberty

“…The onset of puberty is also gated by body energy reserves and nutritional cues (Vazquez, Velasco, & Tena‐Sempere, 2019), and in which, the adipose hormone leptin is an essential signal to the hypothalamic GnRH pulse generator that there are sufficient energy stores in the adipose tissue for fertility to commence, which is necessary for the initiation of puberty (Ahmed, Ong, & Dunger, 2009; Biro, Khoury, & Morrison, 2006; Egan, Inglis, & Anderson, 2017). Leptin stimulates GnRH secretion by binding to the leptin receptor to activates several signaling pathways, including the 5′ adenosine monophosphate‐activated protein kinase (Roa et al, 2018; Xie et al, 2018), mammalian target of rapamycin (mTOR; Roa & Tena‐Sempere, 2010; Roa et al, 2009), phosphoinositide 3‐kinase (PI3K; Garcia‐Galiano, Borges, Allen, & Elias, 2019; Garcia‐Galiano et al, 2017; Nelson et al, 2017; Nguyen, Zacchi, Schulz, Moore, & Fortes, 2018).…”