KNDy neurons as an indirect target of insulin-like growth factor-1

Neurons in the arcuate nucleus of the hypothalamus (ARH) that coexpress kisspeptin, neurokinin B, and dynorphin (KNDy neurons) are considered the gonadotropin-releasing hormone (GnRH) pulse generator necessary for fertility. KNDy neurons are also metabolic sensors controlling the hypothalamic-pituitary-gonadal (HPG) axis. Insulin-like growth factor-1 (IGF-1) secretion is influenced by nutritional status and may serve as a cue detected by neurons to regulate various physiological processes, including reproduction. However, whether IGF-1 modulates KNDy neuron activity remains unclear. RNAscope was used to assess the number of kisspeptin neurons expressing the IGF-1 receptor (IGF1R). Additionally, the effects of IGF-1 on LH secretion, Kiss1 mRNA levels, intracellular calcium concentration ([Ca²⁺]i) in KNDy neurons, and resting membrane potential of kisspeptin neurons were investigated. Kisspeptin cells located at the ARH and anteroventral periventricular and rostral periventricular nuclei (here designated as AVPV) expressed the Igf1r in male and female mice. Intracerebroventricular IGF-1 administration acutely increased LH secretion without altering hypothalamic Kiss1 mRNA in male mice. In brain slices, IGF-1 administration elevated [Ca²⁺]i in KNDy cells of male mice and depolarized KNDy neurons in both sexes. IGF-1-induced depolarization was abolished by TTX and amino acid receptor antagonists, indicating an indirect mechanism. In contrast, IGF-1 has no effect on the RMP of AVPV kisspeptin neurons in female mice. IGF-1 acutely stimulates KNDy neuron activity via indirect effects despite Igf1r expression in these cells. These findings identify IGF-1 as a metabolic signal that modulates KNDy neuron excitability and, consequently, influences the reproductive axis.