DiVall Sara A, Herrera Danny, Sklar Bonnie, Wu Sheng, Wondisford Fredric, Radovick Sally, Wolfe Andrew
Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, United States of America.
PLoS One. 2015 Mar 17;10(3):e0119995. doi: 10.1371/journal.pone.0119995. eCollection 2015.
Infertility associated with obesity is characterized by abnormal hormone release from reproductive tissues in the hypothalamus, pituitary, and ovary. These tissues maintain insulin sensitivity upon peripheral insulin resistance. Insulin receptor signaling may play a role in the dysregulation of gonadotropin-releasing hormone (GnRH) secretion in obesity, but the interdependence of hormone secretion in the reproductive axis and the multi-hormone and tissue dysfunction in obesity hinders investigations of putative contributing factors to the disrupted GnRH secretion. To determine the role of GnRH insulin receptor signaling in the dysregulation of GnRH secretion in obesity, we created murine models of diet-induced obesity (DIO) with and without intact insulin signaling in the GnRH neuron. Obese control female mice were infertile with higher luteinizing hormone levels and higher GnRH pulse amplitude and total pulsatile secretion compared to lean control mice. In contrast, DIO mice with a GnRH specific knockout of insulin receptor had improved fertility, luteinizing hormone levels approaching lean mice, and GnRH pulse amplitude and total secretion similar to lean mice. Pituitary responsiveness was similar between genotypes. These results suggest that in the obese state, insulin receptor signaling in GnRH neurons increases GnRH pulsatile secretion and consequent LH secretion, contributing to reproductive dysfunction.
与肥胖相关的不孕症的特征是下丘脑、垂体和卵巢等生殖组织的激素释放异常。在周围胰岛素抵抗的情况下，这些组织维持胰岛素敏感性。胰岛素受体信号传导可能在肥胖状态下促性腺激素释放激素（GnRH）分泌失调中起作用，但生殖轴中激素分泌的相互依存关系以及肥胖中的多激素和组织功能障碍阻碍了对GnRH分泌紊乱的假定促成因素的研究。为了确定GnRH胰岛素受体信号传导在肥胖状态下GnRH分泌失调中的作用，我们创建了在GnRH神经元中有无完整胰岛素信号传导的饮食诱导肥胖（DIO）小鼠模型。与瘦对照小鼠相比，肥胖对照雌性小鼠不育，促黄体生成素水平更高，GnRH脉冲幅度和总脉冲分泌更高。相比之下，胰岛素受体GnRH特异性敲除的DIO小鼠生育能力有所改善，促黄体生成素水平接近瘦小鼠，GnRH脉冲幅度和总分泌与瘦小鼠相似。各基因型之间垂体反应性相似。这些结果表明，在肥胖状态下，GnRH神经元中的胰岛素受体信号传导增加了GnRH脉冲分泌以及随之而来的LH分泌，导致生殖功能障碍。
