Abstract
Kisspeptin-expressing neurons in the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC) of the hypothalamus relay hormonal and metabolic information to gonadotropin-releasing hormone neurons, which in turn regulate pituitary and gonadal function. Phosphatase and tensin homolog (PTEN) blocks phosphatidylinositol 3-kinase (PI3K), a signaling pathway utilized by peripheral factors to transmit their signals. However, whether PTEN signaling in kisspeptin neurons helps to integrate peripheral hormonal cues to regulate gonadotropin release is unknown. To address this question, we generated mice with a kisspeptin cell-specific deletion of Pten (Kiss-PTEN KO), and first assessed kisspeptin protein expression and gonadotropin release in these animals. Kiss-PTEN KO mice displayed a profound sex and region-specific kisspeptin neuron hyperthrophy. We detected both kisspeptin neuron hyperthrophy as well as increased kisspeptin fiber densities in the AVPV and ARC of Kiss-PTEN KO females and in the ARC of Kiss-PTEN KO males. Moreover, Kiss-PTEN KO mice showed a reduced gonadotropin release in response to gonadectomy. We also found a hyperactivation of mTOR, a downstream PI3K target and central regulator of cell metabolism, in the AVPV and ARC of Kiss-PTEN KO females but not males. Fasting, known to inhibit hypothalamic kisspeptin expression and luteinizing hormone levels, failed to induce these changes in Kiss-PTEN KO females. We conclude that PTEN signaling regulates kisspeptin protein synthesis in both sexes and that its role as a metabolic signaling molecule in kisspeptin neurons is sex-specific.
Highlights
The hypothalamic-pituitary-gonadal (HPG) axis integrates both internal and external signals that influence the reproductive fitness of mammals [1]
Using polymerase chain reaction (PCR), we first confirmed that Cre-mediated deletion of the Pten sequence flanked by LoxP sites was specific to tissues expressing Kiss1 in adult mice of both sexes, including the mediobasal hypothalamus (MBH), the liver, and the gonads, while the deletion allele was not detected in tissues
Phosphatase and tensin homolog (PTEN) switches off the phosphatidylinositol 3-kinase (PI3K) pathway by directly dephosphorylating the second messenger phosphatidylinositol (3,4,5)-triphosphate (PIP3) to phosphatidylinositol (4,5)-bisphosphate (PIP2), resulting in the inhibition of leptin and insulin signaling [13]
Summary
The hypothalamic-pituitary-gonadal (HPG) axis integrates both internal and external signals that influence the reproductive fitness of mammals [1]. Two distinct kisspeptin nuclei have been described: the anteroventral periventricular (AVPV) nucleus and the arcuate (ARC) nucleus Sex steroids, such as estradiol (E2), positively stimulate Kiss gene and peptide expression in the AVPV, whereas the opposite effect is observed in ARC kisspeptin neurons [7]. This region-specific modulation of kisspeptin function by E2 is physiologically relevant as kisspeptin cell-specific estrogen receptor alpha (ERα) signaling is essential for the timing and completion of puberty in females [8], and for E2 positive feedback stimulation of ovulation [9]. The intracellular signaling mechanisms that integrate these signals within kisspeptin neurons remain unclear
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