ESPEYB19 7. Puberty Basic Science (7 abstracts)
7.7. Connecting nutritional deprivation and pubertal inhibition via GRK2-mediated repression of kisspeptin actions in GnRH neurons
Perdices-Lopez C , Avendaño MS , Barroso A , Gaytán F , Ruiz-Pino F , Vázquez MJ , Leon S , Song YB , Sobrino V , Heras V , Romero-Ruiz A , Roa J , Mayor F Jr , Murga C , Pinilla L , Kaiser UB & Tena-Sempere M.
Metabolism. 2022 Apr;129:155141. doi: 10.1016/j.metabol.2022.155141. Epub 2022 Jan 22. PMID: 35074314. https://www.metabolismjournal.com/article/S0026-0495(22)00019-1/fulltext
Brief Summary: the authors used pharmacological and transgenic models to demonstrate the role of GRK2, G protein coupled-receptor kinase-2, as a metabolic modulator of kisspeptin action in GnRH neurons
The awakening of GnRH neurons at puberty is the result of an interplay between complex regulatory mechanisms [1], among which kisspeptin neurons play a master role [2]. While metabolic and nutritional factors are known to influence pubertal timing by affecting presynaptic compounds of kisspeptin signaling [3], postsynaptic regulation of kisspeptin action by metabolic factors also appear critical for puberty [4].
These authors investigated the role of G protein coupled-receptor kinase-2 (GRK2) in GnRH neurons as this GPCR is known to modulate kisspeptin receptor signaling in vitro[5]. GRK2 expression decreased in the preoptic area after pubertal onset in female rats. Postnatal undernutrition induced an increase in hypothalamic GRK2 expression and delayed puberty, and these effects were partially reversed by central administration of a GRK2 inhibitor. Moreover, this central inhibition led to advanced puberty in normally fed female rats and to a higher gonadotrophin response to kisspeptin. Finally, the authors used a transgenic mouse model of conditional ablation of GRK2 in GnRH neurons and observed early onset of puberty, improved gonadotropin response to kisspeptins and increased LH pulse frequency. GRK2 ablation partially prevented the negative impact of undernutrition on puberty onset and LH pulsatility.
Altogether, those in vivo experiments identify GRK2 as a novel modulator of kisspeptin action on GnRH neurons
References: 1. Herbison AE. (2016) “Control of puberty onset and fertility by gonadotropin-releasing hormone neurons.” Nat Rev Endocrinol.; 12:452–66. 2. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. (2012) “Kisspeptins and reproduction: physiological roles and regulatory mechanisms.” Physiol Rev.; 92:1235–316. 3. Navarro VM. (2020) “Metabolic regulation of kisspeptin - the link between energy balance and reproduction.” Nat Rev Endocrinol.; 16(8):407–420. 4. Barroso A, Roa J, Tena-Sempere M. (2019) “Neuropeptide Control of Puberty: Beyond Kisspeptins.” Semin Reprod Med.; 37(4):155–165. 5. Pampillo M, Camuso N, Taylor JE, Szereszewski JM, Ahow MR, Zajac M, Millar RP, Bhattacharya M, Babwah AV. (2009) “Regulation of GPR54 signaling by GRK2 and {beta}-arrestin.” Mol Endocrinol.; 23(12):2060–74.
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ESPE Yearbook of Paediatric Endocrinology
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