Evans Maggie C, Anderson Greg M
Centre for Neuroendocrinology and Department of AnatomyUniversity of Otago School of Medical Sciences, Dunedin, New Zealand
Centre for Neuroendocrinology and Department of AnatomyUniversity of Otago School of Medical Sciences, Dunedin, New Zealand.
J Mol Endocrinol. 2017 Feb;58(2):R107-R128. doi: 10.1530/JME-16-0212. Epub 2017 Jan 5.
Reproductive function in mammals is energetically costly and therefore tightly regulated by nutritional status. To enable this integration of metabolic and reproductive function, information regarding peripheral nutritional status must be relayed centrally to the gonadotropin-releasing hormone (GNRH) neurons that drive reproductive function. The metabolically relevant hormones leptin, insulin and ghrelin have been identified as key mediators of this 'metabolic control of fertility'. However, the neural circuitry through which they act to exert their control over GNRH drive remains incompletely understood. With the advent of Cre-LoxP technology, it has become possible to perform targeted gene-deletion and gene-rescue experiments and thus test the functional requirement and sufficiency, respectively, of discrete hormone-neuron signaling pathways in the metabolic control of reproductive function. This review discusses the findings from these investigations, and attempts to put them in context with what is known from clinical situations and wild-type animal models. What emerges from this discussion is clear evidence that the integration of nutritional signals on reproduction is complex and highly redundant, and therefore, surprisingly difficult to perturb. Consequently, the deletion of individual hormone-neuron signaling pathways often fails to cause reproductive phenotypes, despite strong evidence that the targeted pathway plays a role under normal physiological conditions. Although transgenic studies rarely reveal a critical role for discrete signaling pathways, they nevertheless prove to be a good strategy for identifying whether a targeted pathway is absolutely required, critically involved, sufficient or dispensable in the metabolic control of fertility.
哺乳动物的生殖功能在能量方面代价高昂，因此受到营养状况的严格调控。为了实现代谢功能与生殖功能的这种整合，有关外周营养状况的信息必须传递至中枢，作用于驱动生殖功能的促性腺激素释放激素（GNRH）神经元。代谢相关激素瘦素、胰岛素和胃饥饿素已被确定为这种“生育能力的代谢控制”的关键介质。然而，它们通过何种神经回路对GNRH驱动施加控制，目前仍未完全了解。随着Cre-LoxP技术的出现，进行靶向基因缺失和基因拯救实验成为可能，从而分别测试离散激素-神经元信号通路在生殖功能代谢控制中的功能需求和充分性。本综述讨论了这些研究的结果，并试图将其与临床情况和野生型动物模型中已知的情况相结合。从这次讨论中得出的明显证据是，营养信号对生殖的整合是复杂且高度冗余的，因此，令人惊讶的是，很难被干扰。因此，尽管有充分证据表明靶向通路在正常生理条件下起作用，但单个激素-神经元信号通路的缺失往往不会导致生殖表型。尽管转基因研究很少揭示离散信号通路的关键作用，但它们仍然被证明是一种很好的策略，用于确定靶向通路在生育能力的代谢控制中是否是绝对必需的、至关重要的、足够的或可有可无的。
