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28 January 2017 Gonadotropin-releasing hormone, kisspeptin, and gonadal steroids directly modulate nucleobindin-2/nesfatin-1 in murine hypothalamic gonadotropin-releasing hormone neurons and gonadotropes
A. Hatef, S. Unniappan
Author Affiliations +
Abstract

Neuroendocrine regulation ofmetabolism and reproduction are tightly interlinked. Nesfatin-1 is an 82 amino acidmetabolic peptide derived from nucleobindin-2 (NUCB2). NUCB2 mRNA and protein significantly increase in the hypothalamus of rats during puberty-to-adult transition. Administration of nesfatin-1 modulates circulating LH and testosterone in male rats. However, whether nesfatin-1 acts directly on neurons and gonadotropes remain unknown. In addition, whether reproductive hormones of the hypothalamo-pituitary gonadal axis modulate NUCB2/nesfatin-1 is unclear. To address these, we employed murine hypothalamic (GT1-7) and pituitary (LβT2) cells in vitro. Nucb2 expression, and NUCB2/nesfatin-1 immunoreactivity were observed in both GT1-7 and LβT2 cells, and in the hypothalamus of mice. Nesfatin-1 co-localized GnRH in GT1-7 cells, and in the hypothalamic perikarya of mice. Cells were treated with kisspeptin, GnRH, and estradiol and testosterone, as well as nesfatin-1 for 2, 6 or 24 hours. Synthetic nesfatin-1 increased Kiss1r and Gnrh expression in GT1-7 cells and Lhβ in LβT2. Nesfatin-1 increased GnRH and LHβ protein expression in GT1-7 and LβT2 at 6-hour post incubation respectively. Both NUCB2 mRNA and protein were increased in GT1-7 cells treated with kisspeptin. Testosterone increased NUCB2 mRNA and protein expression in GT1-7 and LβT2. 17β-estradiol increased NUCB2 mRNA and protein expression in LβT2. Nesfatin-1 acts directly on hypothalamic neurons and gonadotropes to elicit a generally positive influence on the endocrine milieu regulating reproduction in mice. Reproductive hormones, in turn, modulate brain and pituitary NUCB2/nesfatin-1. In conclusion, we provide additional information to designate nesfatin-1 as a novel, additional factor that helps reproductive success.

Summary Sentence

Nesfatin-1 has direct stimulatory effects on hypothalamic neurons and gonadotropes to stimulate GnRH, kisspeptin receptor, and LH; and GnRH, kisspeptin, and gonadal steroids elicit similar, stimulatory effects on NUCB2/nesfatin-1.

© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
A. Hatef and S. Unniappan "Gonadotropin-releasing hormone, kisspeptin, and gonadal steroids directly modulate nucleobindin-2/nesfatin-1 in murine hypothalamic gonadotropin-releasing hormone neurons and gonadotropes," Biology of Reproduction 96(3), 635-651, (28 January 2017). https://doi.org/10.1095/biolreprod.116.146621
Received: 4 November 2016; Accepted: 24 January 2017; Published: 28 January 2017
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