SUN-127 - Identifying New Pathways in the Metabolic Control of Puberty

Background/aims: In rodents, hypothalamic KNDy neuron activation during late-juvenile development triggers puberty. Metabolic alterations during the perinatal period can affect the development of hypothalamic KNDy neurons, thereby altering the timing of puberty. Here, we aim to identify the molecular networks of metabolically induced changes in hypothalamic developmental trajectories.

Methods: Female Wistar rats were raised in three metabolic conditions starting at postnatal day (P)0. Undernutrition was modeled by raising rats in large litters (18 pups/dam), overnutrition (ON) was modeled by raising rats in small litters (3 pups/dam), and control animals were raised in normal nutrition (NN) conditions (12 pups/dam). Pubertal timing was determined as the day of vaginal opening and first estrus. RNA sequencing of the arcuate nucleus-median eminence (ARC-ME) at P14, followed by a battery of systems biology approaches, identified metabolically altered gene networks. Networks were further validated at P14-28 by qPCR. Immunofluorescence of perineuronal nets (PNNs) was performed using biotinylated Wisteria floribunda Agglutinin. Oligodendrocyte (OL) populations were identified using Oligodendrocyte Transcription Factor 2, Aspartoacylase, and Myelin Basic Protein.

Results: ON rats showed advanced puberty, increased Kiss1 expression, and increased arborization of KNDy neurons. UN rats showed delayed puberty, reduced Kiss1 expression, and decreased KNDy neuron arborization. RNAseq analysis of the ARC-ME revealed altered Gene Ontology Pathways, including Extracellular Matrix Formation and Organization, Cell Proliferation, and OL Differentiation. Additionally, a single-cell transcriptomic database showed enrichment for genes involved in OL development and cells implicated in PNN assembly. Select PNN and OL gene expression changes were validated in the ARC-ME region across development prior to puberty. Immunofluorescent staining of PNNs showed a marked increase in ARC-ME density in ON and a reduction in UN animals. Moreover, ON animals showed enhanced OL maturation, whereas UN animals showed diminished OL maturation.

Conclusions: Early-life nutritional alterations disturb hypothalamic OL and PNN developmental trajectories, potentially impacting KNDy neuron development and pubertal maturation.

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