ESPE Yearbook of Paediatric Endocrinology

Neuron. 2025 Apr2;113(7):1036-1050.e5. doi: 10.1016/j.neuron.2025.01.015. PMID: 39999843.

Brief summary: This study demonstrates how Agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus (ARC), key hunger sensors, modulate the activity of ARC kisspeptin-expressing neurons (ARC^Kiss neurons), thereby influencing the regulation of puberty onset and reproductive function.

ARC Kiss neurons play a crucial role in puberty initiation by stimulating the release of gonadotropin-releasing hormone (GnRH). AgRP neurons, also located in the ARC, respond to signals of energy deficit, such as fasting, and conversely, are inhibited by signals of energy abundance, like leptin and insulin (1). Consequently, they could be the link between food availability and the initiation of puberty.

The authors used fiber photometry and calcium imaging in freely moving juvenile mice to investigate the dynamic relationship between ARC^Kissneuron activity and ARC^AgRPneuron activity under various nutritional conditions.

In adult mice, ARC^Kiss neurons exhibit pulsatile calcium activity known as synchronous episodes of elevated Ca²⁺ (SEs^Kiss). These SEs^Kiss emerge a few days before the onset of puberty (marked by vaginal opening at postnatal day [PND] 35) in normally nourished female mice, consistent with their proposed role in triggering pubertal initiation. Peripubertal food restriction reduces the frequency of SEs^Kiss and delays pubertal development, as evidenced by delayed vaginal opening and first estrus. Remarkably, restoring food availability after a period of restriction rapidly increases SEs^Kiss frequency within hours and rescues pubertal progression.

To uncover the underlying mechanisms, the authors examined whether ARC^Kissneurons receive monosynaptic inhibitory input that is activated during starvation and relieved by feeding. ARC^Agrp neurons meet these criteria: they are GABAergic, responsive to nutritional status, and form monosynaptic connections with ARC^Kiss neurons, positioning them as plausible mediators of metabolic signals.

Activation of ARC^Agrp neurons suppresses the maturation of SEs^Kiss activity in ARC^Kiss neurons, in part in a body weight–dependent manner, thereby affecting pubertal onset and development. Conversely, inhibition of ARC^Agrp neurons under conditions of chronic food restriction partially restores SEs^Kiss frequency, which may support the occurrence of vaginal opening and the development of antral follicles.

In conclusion, Goto et al. propose a neural circuit that links energy balance to reproductive timing, wherein hunger-sensing ARC^AgRP neurons influence the emergence of pulsatile activity in kisspeptin neurons. However, previous studies suggest that the regulation of pubertal onset by nutritional cues is more complex, likely involving additional parallel pathways operating at different stages of pubertal development(2).

References: 1. Deem JD, Faber CL, Morton GJ. AgRP neurons: Regulators of feeding, energy expenditure, and behavior. FEBS J. 2022 Apr;289(8):2362-2381. doi: 10.1111/febs.16176.2. Anderson GM, Hill JW, Kaiser UB, Navarro VM, Ong KK, Perry JRB, Prevot V, Tena-Sempere M, Elias CF. Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra’s seminal work. Nat Rev Endocrinol. 2024 Feb;20(2):111-123. doi: 10.1038/s41574-023-00919-z. PMID: 38049643.