背景:因为肥胖与脂肪组织增生介导的增加有关,在有丝分裂克隆扩增(MCE)过程中抑制细胞增殖是预防肥胖的主要策略。尽管(-)-羟基柠檬酸(HCA)用于控制肥胖,其对MCE影响的分子机制知之甚少。
目的:本研究旨在探讨HCA对MCE的潜在影响以及影响脂肪生成和肥胖改善的潜在分子机制。
方法:前脂肪细胞系,3T3-L1,用HCA处理;油红O,细胞增殖,细胞周期,并检查了信号通路的相关改变。高脂饮食(HFD)喂养的小鼠给予HCA12周;评估身体和脂肪组织的重量,并在体内检查了表皮白色脂肪组织中信号通路的调节。
结果:这里,我们报告说,在MCE期间,HCA减弱前脂肪细胞系的增殖,3T3-L1,通过将细胞周期阻滞在G0/G1期。此外,HCA显著抑制叉头盒O1(FoxO1)磷酸化,从而诱导细胞周期蛋白依赖性激酶抑制剂1B的表达并抑制细胞周期蛋白依赖性激酶2,细胞周期蛋白E1,增殖细胞核抗原的水平,和磷酸化的视网膜母细胞瘤。重要的是,我们发现核糖体蛋白S6激酶A1(RPS6KA1)影响HCA介导的FoxO1失活及其核排斥.肥胖的动物模型显示,HCA通过抑制脂肪细胞数量以及附睾和肠系膜白色脂肪组织质量来减少高脂饮食诱导的肥胖,这归因于在体外一致鉴定的RPS6KA1,FoxO1,CDKN1B和PCNA的调节。
结论:这些发现为HCA调节脂肪形成的机制提供了新的见解,并强调了RPS6KA1/FoxO1信号轴作为肥胖的治疗靶标。
BACKGROUND: Because obesity is associated with a hyperplasia-mediated increase in adipose tissue, inhibiting cell proliferation during mitotic clonal expansion (MCE) is a leading strategy for preventing obesity. Although (-)-hydroxycitric acid (HCA) is used to control obesity, the molecular mechanisms underlying its effects on MCE are poorly understood.
OBJECTIVE: This study aimed to investigate the potential effects of HCA on MCE and underlying molecular mechanisms affecting adipogenesis and obesity improvements.
METHODS: Preadipocyte cell line, 3T3-L1, were treated with HCA; oil red O, cell proliferation, cell cycle, and related alterations in signaling pathways were examined. High-fat diet (HFD)-fed mice were administered HCA for 12 weeks; body and adipose tissues weights were evaluated, and the regulation of signaling pathways in epidydimal white adipose tissue were examined in vivo.
RESULTS: Here, we report that during MCE, HCA attenuates the proliferation of the preadipocyte cell line, 3T3-L1, by arresting the cell cycle at the G0/G1 phase. In addition, HCA markedly inhibits Forkhead Box O1 (FoxO1) phosphorylation, thereby inducing the expression of cyclin-dependent kinase inhibitor 1B and suppressing the levels of cyclin-dependent kinase 2, cyclin E1, proliferating cell nuclear antigen, and phosphorylated retinoblastoma. Importantly, we found that ribosomal protein S6 kinase A1 (RPS6KA1) influences HCA-mediated inactivation of FoxO1 and its nuclear exclusion. An animal model of obesity revealed that HCA reduced high-fat diet-induced obesity by suppressing adipocyte numbers as well as epididymal and mesenteric white adipose tissue mass, which is attributed to the regulation of RPS6KA1, FoxO1, CDKN1B and PCNA that had been consistently identified in vitro.
CONCLUSIONS: These findings provide novel insights into the mechanism by which HCA regulates adipogenesis and highlight the RPS6KA1/FoxO1 signaling axis as a therapeutic target for obesity.