Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, and Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115.
J Neurosci. 2014 Apr 23;34(17):6047-56. doi: 10.1523/JNEUROSCI.3003-13.2014.
The adipocyte-derived hormone leptin plays a critical role in the central transmission of energy balance to modulate reproductive function. However, the neurocircuitry underlying this interaction remains elusive, in part due to incomplete knowledge of first-order leptin-responsive neurons. To address this gap, we explored the contribution of predominantly inhibitory (GABAergic) neurons versus excitatory (glutamatergic) neurons in the female mouse by selective ablation of the leptin receptor in each neuronal population: Vgat-Cre;Lepr(lox/lox) and Vglut2-Cre;Lepr(lox/lox) mice, respectively. Female Vgat-Cre;Lepr(lox/lox) but not Vglut2-Cre;Lepr(lox/lox) mice were obese. Vgat-Cre;Lepr(lox/lox) mice had delayed or absent vaginal opening, persistent diestrus, and atrophic reproductive tracts with absent corpora lutea. In contrast, Vglut2-Cre;Lepr(lox/lox) females exhibited reproductive maturation and function comparable to Lepr(lox/lox) control mice. Intracerebroventricular administration of kisspeptin-10 to Vgat-Cre;Lepr(lox/lox) female mice elicited robust gonadotropin responses, suggesting normal gonadotropin-releasing hormone neuronal and gonadotrope function. However, adult ovariectomized Vgat-Cre;Lepr(lox/lox) mice displayed significantly reduced levels of Kiss1 (but not Tac2) mRNA in the arcuate nucleus, and a reduced compensatory luteinizing hormone increase compared with control animals. Estradiol replacement after ovariectomy inhibited gonadotropin release to a similar extent in both groups. These animals also exhibited a compromised positive feedback response to sex steroids, as shown by significantly lower Kiss1 mRNA levels in the AVPV, compared with Lepr(lox/lox) mice. We conclude that leptin-responsive GABAergic neurons, but not glutamatergic neurons, act as metabolic sensors to regulate fertility, at least in part through modulatory effects on kisspeptin neurons.
脂肪细胞衍生的激素瘦素在调节生殖功能的能量平衡中枢传递中起着关键作用。然而，这种相互作用的神经回路仍然难以捉摸，部分原因是对一级瘦素反应神经元的了解不完整。为了解决这一差距，我们通过选择性消融每种神经元群体中的瘦素受体，分别探索了主要抑制性（GABA 能）神经元与兴奋性（谷氨酸能）神经元的贡献：Vgat-Cre；Lepr(lox/lox) 和 Vglut2-Cre；Lepr(lox/lox) 小鼠。雌性 Vgat-Cre；Lepr(lox/lox) 但不是 Vglut2-Cre；Lepr(lox/lox) 小鼠肥胖。Vgat-Cre；Lepr(lox/lox) 小鼠的阴道开口延迟或缺失，持续处于动情期，生殖道萎缩，无黄体。相比之下，Vglut2-Cre；Lepr(lox/lox) 雌性表现出与 Lepr(lox/lox) 对照小鼠相当的生殖成熟和功能。将 kisspeptin-10 鞘内给予 Vgat-Cre；Lepr(lox/lox) 雌性小鼠可引起促性腺激素的强烈反应，表明 GnRH 神经元和促性腺激素的正常功能。然而，成年卵巢切除的 Vgat-Cre；Lepr(lox/lox) 小鼠的弓状核中 Kiss1（而非 Tac2）mRNA 水平显著降低，与对照动物相比，促黄体生成素的代偿性增加减少。卵巢切除后雌激素替代治疗对两组的促性腺激素释放抑制作用相似。这些动物还表现出对性类固醇的正反馈反应受损，与 Lepr(lox/lox) 小鼠相比，AVPV 中的 Kiss1 mRNA 水平显著降低。我们得出结论，瘦素反应性 GABA 能神经元而非谷氨酸能神经元作为代谢传感器调节生育能力，至少部分通过对 kisspeptin 神经元的调节作用。
