INRAE UMR85 Physiologie de la Reproduction et des Comportements, Nouzilly, France; CNRS UMR7247 Physiologie de la Reproduction et des Comportements, Nouzilly, France; Université de Tours, Tours, France; IFCE, Nouzilly, France.
Molecular Endocrinology and Rare Diseases, University Hospital, Claude Bernard Lyon 1 University, Bron, France.
Mol Cell Endocrinol. 2021 Jan 15;520:111080. doi: 10.1016/j.mce.2020.111080. Epub 2020 Nov 12.
During obesity, excess body weight is not only associated with an increased risk of type 2-diabetes, but also several other pathological processes, such as infertility. Adipose tissue is the largest endocrine organ of the body that produces adipokines, including adiponectin. Adiponectin has been reported to control fertility through the hypothalamic-pituitary-gonadal axis, and folliculogenesis in the ovaries. In this study, we focused on a recent adiponectin-like synthetic agonist called AdipoRon, and its action in human luteinized granulosa cells. We demonstrated that AdipoRon activated the adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor alpha (PPAR) signalling pathways in human luteinized granulosa cells. A 25 μM AdipoRon stimulation reduced granulosa cell proliferation by inducing cell cycle arrest in G, associated with PTEN and p53 pathway activation. In addition, AdipoRon perturbed cell metabolism by decreasing mitochondrial activity and ATP production. In human luteinized granulosa cells, AdipoRon increased phosphodiesterase activity, leading to a drop in cyclic adenosine monophosphate (cAMP) production, aromatase expression and oestrogens secretion. In conclusion, AdipoRon impacted folliculogenesis by altering human luteinized granulosa cell function, via steroid production and cell proliferation. This agonist may have applications for improving ovarian function in metabolic disorders or granulosa cancers.
在肥胖症中，多余的体重不仅与 2 型糖尿病风险增加有关，还与其他几种病理过程有关，如不孕。脂肪组织是人体最大的内分泌器官，可产生脂联素等脂肪因子。脂联素已被报道通过下丘脑-垂体-性腺轴和卵巢中的卵泡发生来控制生育能力。在这项研究中，我们专注于一种最近的脂联素样合成激动剂，称为 AdipoRon，及其在人黄体化颗粒细胞中的作用。我们证明 AdipoRon 激活了人黄体化颗粒细胞中的腺苷单磷酸激活蛋白激酶 (AMPK) 和过氧化物酶体增殖物激活受体α (PPAR) 信号通路。25 μM 的 AdipoRon 刺激通过诱导细胞周期停滞在 G 期来减少颗粒细胞增殖，与 PTEN 和 p53 通路的激活有关。此外，AdipoRon 通过降低线粒体活性和 ATP 产生来改变细胞代谢。在人黄体化颗粒细胞中，AdipoRon 通过增加磷酸二酯酶活性，导致环腺苷酸 (cAMP) 产生、芳香酶表达和雌激素分泌下降。总之，AdipoRon 通过改变人黄体化颗粒细胞的功能，通过类固醇产生和细胞增殖来影响卵泡发生。这种激动剂可能在改善代谢紊乱或颗粒细胞癌中的卵巢功能方面有应用前景。
