EARLY-ONSET OBESITY ALTERS TRANSCRIPTOMIC SIGNATURES AND NEURONAL ACTIVITY OF KISS1<SUP>ARC</SUP> NEURONS DURING PUBERTAL MATURATION

Puberty, as key maturational event required to achieve reproductive competence, is strongly influenced by nutritional conditions. Sufficient energy stores are required to activate the hypothalamic-pituitary-gonadal axis at puberty, whereas obesity can perturb pubertal timing. Accumulating evidence suggests that Kiss1 neurons at the hypothalamic Arcuate nucleus (Kiss1^ARC) integrate metabolic cues and play an important role in the control of puberty and reproduction. Yet, how obesity alters the molecular and functional identity of Kiss1 neurons during critical windows of pubertal development remains largely unknown.
We evaluate herein how early-onset obesity impacts puberty, by a combination of expression and functional analyses targeting Kiss1^ARC neurons. To this end, we have developed a model of early obesity and precocious puberty in female mice expressing the tdTomato fluorescent reporter selectively in Kiss1 neurons. In this model, we isolated Kiss1^ARC neurons by fluorescence-activated cell sorting (FACS) followed by RNA-seq profiling at the prepubertal and peripubertal stages, under normo-nutrition and obesity. In addition, electrophysiological recordings of Kiss1^ARC neurons were conducted in these conditions.
Transcriptomic analysis revealed obesity-dependent changes in Kiss1^ARC neurons in the expression of genes associated with synaptic organization and neurotransmission, suggesting alteration in synaptic-related pathways due to obesity. In turn, electro-physiological recordings documented significant changes in neuronal excitability, specifically on intrinsic firing properties, at the prepubertal stage associated with obesity. Together, our transcriptomic and electrophysiological results indicate that early-onset obesity is associated with molecular and functional alterations in Kiss1^ARC neurons during pubertal development, which seeming play a major role in dysregulation of puberty under obese conditions.