Reproductive Developmental Biology Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, IL, USA.
FASEB J. 2021 Aug;35(8):e21770. doi: 10.1096/fj.202100304R.
Steroid hormones regulate various aspects of physiology, from reproductive functions to metabolic homeostasis. Steroidogenic factor-1 (NR5A1) plays a central role in the development of steroidogenic tissues and their ability to produce steroid hormones. Inactivation of Nr5a1 in the mouse results in a complete gonadal and adrenal agenesis, absence of gonadotropes in the pituitary and impaired development of ventromedial hypothalamus, which controls glucose and energy metabolism. In this study, we set out to examine the consequences of NR5A1 overexpression (NR5A1+) in the NR5A1-positive cell populations in female mice. Ovaries of NR5A1+ females presented defects such as multi-oocyte follicles and an accumulation of corpora lutea. These females were hyperandrogenic, had irregular estrous cycles with persistent metestrus and became prematurely infertile. Furthermore, the decline in fertility coincided with weight gain, increased adiposity, hypertriglyceridemia, hyperinsulinemia, and impaired glucose tolerance, indicating defects in metabolic functions. In summary, excess NR5A1 expression causes hyperandrogenism, disruption of ovarian functions, premature infertility, and disorders of metabolic homeostasis. This NR5A1 overexpression mouse provides a novel model for studying not only the molecular actions of NR5A1, but also the crosstalk between endocrine, reproductive, and metabolic systems.
甾体激素调节着从生殖功能到代谢稳态等各个生理方面。甾体生成因子-1（NR5A1）在甾体生成组织的发育及其产生甾体激素的能力中发挥着核心作用。Nr5a1 在小鼠中的失活导致完全的性腺和肾上腺发育不全、垂体促性腺激素缺乏以及控制葡萄糖和能量代谢的下丘脑腹内侧区发育受损。在这项研究中，我们着手研究了 NR5A1 在雌性小鼠 NR5A1 阳性细胞群中的过表达（NR5A1+）的后果。NR5A1+ 雌性的卵巢表现出多卵母细胞卵泡和黄体堆积等缺陷。这些雌性动物表现出高雄激素血症，动情周期不规则，持续处于动情后期，并过早地失去生育能力。此外，生育能力的下降伴随着体重增加、肥胖增加、高三酰甘油血症、高胰岛素血症和葡萄糖耐量受损，表明代谢功能出现缺陷。总之，NR5A1 表达过多会导致高雄激素血症、卵巢功能紊乱、过早不孕以及代谢稳态失调。这种 NR5A1 过表达小鼠为研究 NR5A1 的分子作用以及内分泌、生殖和代谢系统之间的相互作用提供了一个新的模型。
