School of Medicine, Chongqing University, Chongqing, 400044, China.
Department of Endocrinology, Chongqing University Three Gorges Hospital, Chongqing, 404000, China.
J Ovarian Res. 2024 Nov 19;17(1):229. doi: 10.1186/s13048-024-01554-6.
Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder accompanied by ovulatory dysfunction. Insulin resistance (IR) is a key pathogenic mechanism in PCOS, and insulin sensitizers, such as metformin and pioglitazone, can improve PCOS symptoms. Chiglitazar, a pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist, is also an insulin sensitizer; however, its therapeutic effects have not yet been studied in PCOS. We evaluated the therapeutic effects of chiglitazar in a rat model of PCOS.
Sprague-Dawley rats aged 4 weeks were injected subcutaneously with dehydroepiandrosterone (DHEA) (6 mg/100 g/day) to establish PCOS, and a control (CON) group was established. The rats were divided into the CON, PCOS model (DHEA), pioglitazone-treated (DHEA + PIO), and chiglitazar-treated (DHEA + CHI) groups. The DHEA + PIO group received pioglitazone (20 mg/kg/day) and the DHEA + CHI group received chiglitazar (20 mg/kg/day), each for 15 days. Body weight, estrous cycle, and glucose tolerance test (GTT) and insulin resistance test (ITT) results were monitored. Experimental animal energy metabolism systems were utilized to assess metabolic parameters. Enzyme-linked immunosorbent assay was conducted to detect changes in serum hormones, including insulin, adiponectin, sex-related hormones, and lipid metabolism indicators. The ovaries were used for molecular biology experiments to detect changes in Akt/phosphorylated Akt and glucose transporter 4 (GLUT4) expression by Western blotting and quantitative polymerase chain reaction.
Chiglitazar and pioglitazone improved PCOS symptoms. However, chiglitazar demonstrated a more pronounced effect on lipid improvement and weight gain than pioglitazone. In the DHEA + PIO and DHEA + CHI groups, there was notable recovery in oxygen consumption and carbon dioxide output; substantial improvement in GTT and ITT results; an increase in adiponectin; and a reduction in serum insulin, androgens, luteinizing hormone (LH), and LH/follicle-stimulating hormone ratio. Compared with the DHEA group, the DHEA + CHI group exhibited notable decreases in triglycerides, free fatty acids, and atherosclerosis index, while the DHEA + PIO group demonstrated no changes. Granulosa cells and healthy follicles increased in ovarian sections. Ovarian steroidogenic enzymes also increased in the DHEA + PIO and DHEA + CHI groups compared with the DHEA group. Mechanistically, chiglitazar increased Akt phosphorylation.
Chiglitazar significantly improved ovulation in rats with PCOS and may be a potential novel therapeutic strategy for PCOS.
多囊卵巢综合征（PCOS）是一种伴有排卵功能障碍的内分泌和代谢紊乱疾病。胰岛素抵抗（IR）是 PCOS 的关键发病机制，胰岛素增敏剂如二甲双胍和吡格列酮可改善 PCOS 症状。曲格列酮，一种全过氧化物酶体增殖物激活受体（pan-PPAR）激动剂，也是一种胰岛素增敏剂；然而，其在 PCOS 中的治疗效果尚未得到研究。我们评估了曲格列酮在 PCOS 大鼠模型中的治疗效果。
4 周龄 Sprague-Dawley 大鼠皮下注射脱氢表雄酮（DHEA）（6mg/100g/天）建立 PCOS，并建立对照组（CON）。大鼠分为对照组（CON）、PCOS 模型（DHEA）、吡格列酮治疗组（DHEA+PIO）和曲格列酮治疗组（DHEA+CHI）。DHEA+PIO 组给予吡格列酮（20mg/kg/天），DHEA+CHI 组给予曲格列酮（20mg/kg/天），均治疗 15 天。监测体重、发情周期、葡萄糖耐量试验（GTT）和胰岛素抵抗试验（ITT）结果。利用实验动物能量代谢系统评估代谢参数。酶联免疫吸附试验检测血清激素变化，包括胰岛素、脂联素、性激素和脂质代谢指标。取卵巢进行分子生物学实验，通过 Western blot 和定量聚合酶链反应检测 Akt/磷酸化 Akt 和葡萄糖转运蛋白 4（GLUT4）的表达变化。
曲格列酮和吡格列酮改善了 PCOS 症状。然而，曲格列酮在改善脂质和体重增加方面的效果比吡格列酮更为显著。在 DHEA+PIO 和 DHEA+CHI 组中，氧耗和二氧化碳排出量显著恢复；GTT 和 ITT 结果明显改善；脂联素增加；血清胰岛素、雄激素、黄体生成素（LH）和 LH/卵泡刺激素比值降低。与 DHEA 组相比，DHEA+CHI 组甘油三酯、游离脂肪酸和动脉粥样硬化指数明显降低，而 DHEA+PIO 组无变化。卵巢切片中颗粒细胞和健康卵泡增加。卵巢甾体生成酶在 DHEA+PIO 和 DHEA+CHI 组也较 DHEA 组增加。在机制上，曲格列酮增加了 Akt 的磷酸化。
曲格列酮显著改善了 PCOS 大鼠的排卵功能，可能是 PCOS 的一种潜在新型治疗策略。
