Regulation of Kisspeptin Synthesis and Release in the Preoptic/Anterior Hypothalamic Region of Prepubertal Female Rats: Actions of IGF‐1 and Alcohol

Background Alcohol (ALC) causes suppressed secretion of prepubertal luteinizing hormone‐releasing hormone (LHRH). Insulin‐like growth factor‐1 (IGF‐1) and kisspeptin (Kp) are major regulators of LHRH and are critical for puberty. IGF‐1 may be an upstream mediator of Kp in the preoptic area and rostral hypothalamic area (POA/RHA) of the rat brain, a region containing both Kp and LHRH neurons. We investigated the ability of IGF‐1 to stimulate prepubertal Kp synthesis and release in POA/RHA, and the potential inhibitory effects of ALC. Methods Immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 0730 hours. At 0900 hours, both groups were subdivided where half received either saline or IGF‐1 into the brain third ventricle. A second dose of ALC (2 g/kg) or water was administered at 1130 hours. Rats were killed 6 hours after injection and POA/RHA region collected. Results IGF‐1 stimulated Kp, an action blocked by ALC. Upstream to Kp, IGF‐1 receptor (IGF‐1R) activation, as demonstrated by the increase in insulin receptor substrate 1, resulted in activation of Akt, tuberous sclerosis 2, ras homologue enriched in brain, and mammalian target of rapamycin (mTOR). ALC blocked the central action of IGF‐1 to induce their respective phosphorylation. IGF‐1 specificity and ALC specificity for the Akt‐activated mTOR pathway were demonstrated by the absence of effects on PRAS40. Furthermore, IGF‐1 stimulated Kp release from POA/RHA incubated in vitro. Conclusions IGF‐1 stimulates prepubertal Kp synthesis and release following activation of a mTOR signaling pathway, and ALC blocks this pathway at the level of IGF‐1R. Our study demonstrates the ability of IGF‐1 to stimulate the prepubertal synthesis and release of kisspeptin, by activating an IGF‐1 receptor/Akt mediated signaling pathway within the hypothalamus. Importantly, alcohol was shown to act at the level of the IGF‐1 receptor to block the downstream components of this pathway. Since kisspeptin is a critical regulator of LHRH, this action, at least in part, contributes to the alcohol‐induced suppression in LHRH at the time of puberty.