<br>GIP 和 GLP-1 受体以及肠-性腺轴参与调节小鼠雌性生殖功能的证据。,Biomolecules

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GIP 和 GLP-1 受体以及肠-性腺轴参与调节小鼠雌性生殖功能的证据。
Biomolecules ( IF 4.8 ) Pub Date : 2022-11-23 , DOI: 10.3390/biom12121736
Dawood Khan ₁ , Opeolu O Ojo _{1,

2} , Orla Rm Woodward ₃ , Jo Edward Lewis ₃ , Ananyaa Sridhar ₁ , Fiona M Gribble ₃ , Frank Reimann ₃ , Peter R Flatt ₁ , R Charlotte Moffett ₁

Affiliation

大量证据表明生殖轴和肠轴之间存在串扰，但代谢和生殖之间的联系机制仍不清楚。本研究通过检查受体分布以及全局 GIPR 和 GLP-1R 缺失对生殖功能的影响，评估了葡萄糖依赖性促胰岛素多肽 (GIP) 和胰高血糖素样肽-1 (GLP-1) 在生殖功能中的可能作用。小鼠的动情周期和生殖结果。通过 PCR 可以轻松检测女性生殖组织（包括垂体、卵巢和子宫角）中的 GIPR 和 GLP-1R 基因表达。使用 GIPR-Cre 和 GLP1R-Cre 小鼠通过肠降血糖素受体的组织学可视化证实蛋白质表达，其中肠降血糖素受体表达细胞被荧光标记。功能研究表明，与野生型对照相比，雌性 GIPR-/- 和 GLP-1R-/- 缺失小鼠表现出显着（p < 0.05 和 p < 0.01）紊乱的动情周期，表明生育能力降低。此外，在三个繁殖周期中，只有 50% 和 16% 的雌性 GIPR-/- 和 GLP-1R-/- 小鼠分别与野生型雄性小鼠产下后代。与肠促胰素受体在妊娠结局中的生理作用一致，GIPR-/- 和 GLP-1R-/- 小鼠的窝产仔数显着减少 (p < 0.001-p < 0.05)。口服二甲双胍（300 mg/kg 体重）（一种临床上用于治疗 PCOS 的药物）治疗另外两个繁殖期，妊娠结局没有改善，但 GIPR-/- 组的产仔数大约是原来的 2 倍。第二个繁殖周期更大。这些数据强调了肠促胰岛素受体在调节女性生殖功能中的重要性，这可能为生殖疾病的药物干预提供未来的目标。

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Evidence for Involvement of GIP and GLP-1 Receptors and the Gut-Gonadal Axis in Regulating Female Reproductive Function in Mice.

Substantial evidence suggests crosstalk between reproductive and gut-axis but mechanisms linking metabolism and reproduction are still unclear. The present study evaluated the possible role of glucose-dependent-insulinotropic-polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) in reproductive function by examining receptor distribution and the effects of global GIPR and GLP-1R deletion on estrous cycling and reproductive outcomes in mice. GIPR and GLP-1R gene expression were readily detected by PCR in female reproductive tissues including pituitary, ovaries and uterine horn. Protein expression was confirmed with histological visualisation of incretin receptors using GIPR-Cre and GLP1R-Cre mice in which the incretin receptor expressing cells were fluorescently tagged. Functional studies revealed that female GIPR-/- and GLP-1R-/- null mice exhibited significantly (p < 0.05 and p < 0.01) deranged estrous cycling compared to wild-type controls, indicative of reduced fertility. Furthermore, only 50% and 16% of female GIPR-/- and GLP-1R-/- mice, respectively produced litters with wild-type males across three breeding cycles. Consistent with a physiological role of incretin receptors in pregnancy outcome, litter size was significantly (p < 0.001-p < 0.05) decreased in GIPR-/- and GLP-1R-/- mice. Treatment with oral metformin (300 mg/kg body-weight), an agent used clinically for treatment of PCOS, for a further two breeding periods showed no amelioration of pregnancy outcome except that litter size in the GIPR-/- group was approximately 2 times greater in the second breeding cycle. These data highlight the significance of incretin receptors in modulation of female reproductive function which may provide future targets for pharmacological intervention in reproductive disorders.

更新日期：2022-11-23

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