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Involvement of hypothalamic kisspeptin neurons in reproductive dysfunctions due to changes in the GH-IGF-1 axis

Grant number: 22/11262-5
Support Opportunities:Regular Research Grants
Duration: April 01, 2023 - March 31, 2025
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Renata Frazão
Grantee:Renata Frazão
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated researchers: Jones Bernardes Graceli


Kisspeptins are considered the main neuromodulators of gonadotropin-releasing hormone neurons (GnRH). Neurons expressing the Kiss1 gene located in the anteroventral periventricular nucleus and the rostral periventricular nucleus (AVPV/PeN) and arcuate nucleus of the hypothalamus (ARH) secrete kisspeptins, coexpress estrogen receptor alpha, and project to GnRH neurons. Hypothalamic kisspeptin neurons modulate the negative and positive estradiol feedback through GnRH activity contributing to estrous/menstrual cycle regulation. ARH kisspeptin neurons are responsible for the negative feedback during most of the estrous/menstrual cycle, in addition to being responsible for the rhythmic, pulsatile pattern of GnRH secretion. On the other hand, AVPV/PeN kisspeptin neurons are responsible for the positive feedback being responsible to induce the peak of GnRH secretion, and consequently, gonadotropins, required for ovulation. Many studies were performed to understand how different factors (such as hormones) can affect the activity of kisspeptin neurons and, therefore, the hypothalamic-pituitary-gonadal (HPG) axis. Experimental animals, or humans, that exhibit growth hormone (GH) deficiency, or GH resistance, for example, show a significant delay in sexual maturation and infertility. On the other hand, the administration of exogenous GH anticipates puberty and increases the pregnancy rate of in vitro fertilization treatments. Suggesting that among GH functions this hormone can modulate reproduction. Our research group has demonstrated that AVPV/PeN kisspeptin neurons are directly responsive to GH. Furthermore, we demonstrated that GH signaling in kisspeptin neurons during puberty modulates the expression of genes essential for the HPG axis, such as the Kiss1 and Gnrh1 genes. Considering that AVPV/PeN kisspeptin neurons are GH-responsive, our current hypothesis predicts that alterations in GH secretion and/or signaling during development are sufficient to modulate the activity of kisspeptin neurons and, consequently, induce reproductive deficits. Additionally, it is important to consider that GH may provide indirect signaling to kisspeptin cells, among others cells type, since this hormone induces the synthesis of insulin-like growth factor 1 (IGF-1). However, it is unknown whether IGF-1 modulates the hypothalamic kisspeptin neuron activity somehow. In the present study, we will use neuroanatomical, electrophysiological, and genetically modified animal strategies to assess whether reproductive deficits associated with changes in secretion and/or signaling of the GH-IGF-1 axis occur due to impaired kisspeptin neurons activity. If the activity of kisspeptin neurons can be modulated as a result of alterations in the signaling of the GH-IGF-1 axis, we will test whether treatment with kisspeptins or Kiss1r receptor agonists, which have great therapeutic potential in the treatment of reproductive disorders, may prevent reproductive deficits in mice. (AU)

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