Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, PR China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China.
Eur J Pharmacol. 2022 Jun 15;925:175002. doi: 10.1016/j.ejphar.2022.175002. Epub 2022 May 5.
The abnormal proliferation and hypertrophy of adipocytes mediate the expansion of adipose tissue and then cause obesity-related diseases. Theoretically, an approach for preventing and curing obesity is to inhibit cell proliferation during the mitotic clonal expansion (MCE) progression of adipocyte differentiation. Polycyclic polyprenylated acylphloroglucinols (PPAPs) are mainly found from Hypericum and Garcinia genus, which have been reported to have various biological activities such as anti-depressant, anti-oxidant, and anti-tumor. Previously, our group has reported that adamantane-type PPAPs exhibited blunting activity in adipogenesis. In this study, another six adamantane PPAPs were screened to investigate their anti-adipogenesis activities and then discussed the structure-activity relationship. Particularly, sampsonione F, one of the PPAPs dramatically suppressed adipogenesis dose-dependently in vitro, along with decreased expressions of C/EBPβ, C/EBPα, PPARγ, FABP4, and FAS. Moreover, sampsonione F upregulated the expression of p27 by activating p53 pathway and then downregulated the expressions of key regulators during G1/S phase arrest. Our data support that sampsonione F suppressed adipogenesis by activating p53 pathway, regulating cyclins, and resulting in G1/S phase arrest during the MCE progression of adipogenesis. This work provides a new adamantane-type PPAPs in the regulation of adipogenesis and extends our knowledges on the mechanism of the type PPAPs in regulation of adipogenesis.
脂肪细胞的异常增殖和肥大介导了脂肪组织的扩张，进而导致与肥胖相关的疾病。从理论上讲，预防和治疗肥胖的一种方法是在脂肪细胞分化的有丝分裂克隆扩张（MCE）过程中抑制细胞增殖。多环多聚异戊二烯基酰基间苯三酚（PPAPs）主要存在于贯叶连翘属和藤黄属植物中，据报道具有各种生物活性，如抗抑郁、抗氧化和抗肿瘤。以前，我们的研究小组已经报道了金刚烷型 PPAPs 在脂肪生成中具有钝化活性。在这项研究中，我们筛选了另外六种金刚烷型 PPAPs 来研究它们的抗脂肪生成活性，并讨论了结构-活性关系。特别是，PPAPs 中的 sampsonione F 显著地以剂量依赖的方式抑制体外脂肪生成，同时降低了 C/EBPβ、C/EBPα、PPARγ、FABP4 和 FAS 的表达。此外，sampsonione F 通过激活 p53 通路上调了 p27 的表达，从而下调了 G1/S 期阻滞期间关键调节剂的表达。我们的数据支持了 sampsonione F 通过激活 p53 通路、调节细胞周期蛋白来抑制脂肪生成，并导致脂肪生成的 MCE 过程中 G1/S 期阻滞。这项工作提供了一种新的金刚烷型 PPAPs 来调节脂肪生成，并扩展了我们对该类型 PPAPs 调节脂肪生成机制的认识。
