Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Goryeodae-Ro, Seongbuk-Gu, Seoul, 02841, Republic of Korea.
Sci Rep. 2023 Feb 2;13(1):1943. doi: 10.1038/s41598-023-28260-5.
The present study aimed to investigate whether time-restricted feeding (TRF) ameliorates metabolic and reproductive phenotypes in a letrozole-induced mouse model of polycystic ovary syndrome (PCOS). Sixty female C57BL/6 N mice were randomly divided into two groups according to the type of food received: either a chow or a 60% high-fat diet. Those mice were subcutaneously implanted with letrozole or placebo pellets at four weeks of age. Then, letrozole-treated mice were randomly assigned to different feeding regimens: (1) TRF for 4 h (ZT12-ZT16) or (2) ad libitum diet. After 4 weeks of dietary intervention, estrous cycles were determined with daily vaginal smear examination, and serial tail-tip blood sampling was performed at 5-min intervals for 2 h to measure the luteinizing hormone (LH) pulse frequency, amplitude, and mean LH levels in the diestrus cycle stage. Letrozole-treated mice in the ad libitum group demonstrated multiple PCOS-like phenotypes including ovulatory dysfunction, polycystic ovaries, and increased body weight, parametrial fat weight, adipocyte size and inflammation, and higher expression of Cyp17, Cyp19, and Fshr in the ovary, and Kiss1r and Gnrh in the hypothalamus, elevated serum testosterone levels, and more rapid and elevated LH pulsatility, with increased pulse frequency, amplitude, and mean levels in the diestrus stage, compared with the controls. After TRF for 4 weeks, those phenotypes reverted to normal levels in letrozole-treated mice, except the percentage of diestrus cycles indicating the arrest of estrous cycling which did not differ between the TRF and ad libitum groups. Our results demonstrate that TRF has therapeutic effects on the reproductive and metabolic phenotypes of a letrozole-induced mouse model of PCOS.
本研究旨在探讨限时喂养（TRF）是否能改善他莫昔芬诱导的多囊卵巢综合征（PCOS）小鼠模型的代谢和生殖表型。60 只 C57BL/6N 雌性小鼠根据所接受的食物类型随机分为两组：普通饲料组或 60%高脂肪饮食组。这些小鼠在 4 周龄时皮下植入他莫昔芬或安慰剂微球。然后，他莫昔芬处理的小鼠被随机分配到不同的喂养方案中：（1）限时喂养 4 小时（ZT12-ZT16）或（2）自由进食。经过 4 周的饮食干预后，通过每日阴道涂片检查确定动情周期，并在动情周期的静止期每隔 5 分钟进行 2 小时的连续尾尖采血，以测量黄体生成素（LH）脉冲频率、幅度和平均 LH 水平。自由进食组的他莫昔芬处理小鼠表现出多种 PCOS 样表型，包括排卵功能障碍、多囊卵巢和体重增加、宫旁脂肪重量增加、脂肪细胞大小和炎症增加，以及卵巢中 Cyp17、Cyp19 和 Fshr 的表达增加，下丘脑 Kiss1r 和 Gnrh 的表达增加，血清睾酮水平升高，LH 脉冲性更迅速和升高，静止期的脉冲频率、幅度和平均水平增加，与对照组相比。经过 4 周的 TRF 后，除了动情周期的静止期指示发情周期停止的比例在 TRF 组和自由进食组之间没有差异外，他莫昔芬处理小鼠的这些表型恢复到正常水平。我们的结果表明，TRF 对他莫昔芬诱导的 PCOS 小鼠模型的生殖和代谢表型具有治疗作用。
