Bisphenol A (BPA), which is used in a variety of consumer-related plastic products, was reported to cause adverse effects, including disruption of adipocyte differentiation, interference with obesity mechanisms, and impairment of insulin- and glucose homeostasis. Substitute compounds are increasingly emerging but are not sufficiently investigated. We aimed to investigate the mode of action of BPA and four of its substitutes during the differentiation of human preadipocytes to adipocytes and their molecular interaction with peroxisome proliferator-activated receptor γ (PPARγ), a pivotal regulator of adipogenesis. Binding and effective biological activation of PPARγ were investigated by surface plasmon resonance and reporter gene assay, respectively. Human preadipocytes were continuously exposed to BPA, BPS, BPB, BPF, BPAF, and the PPARγ-antagonist GW9662. After 12 days of differentiation, lipid production was quantified via Oil Red O staining, and global protein profiles were assessed using LC-MS/MS-based proteomics. All tested bisphenols bound to human PPARγ with similar efficacy as the natural ligand 15d-PGJ2 in vitro and provoked an antagonistic effect on PPARγ in the reporter gene assay at non-cytotoxic concentrations. During the differentiation of human preadipocytes, all bisphenols decreased lipid production. Global proteomics displayed a down-regulation of adipogenesis and metabolic pathways, similar to GW9662. Interestingly, pro-inflammatory pathways were up-regulated, MCP1 release was increased, and adiponectin decreased. pAKT/AKT ratios revealed significantly reduced insulin sensitivity by BPA, BPB, and BPS upon insulin stimulation. Thus, our results show that not only BPA but also its substitutes disrupt crucial metabolic functions and insulin signaling in adipocytes under low, environmentally relevant concentrations. This effect, mediated through inhibition of PPARγ, may promote hypertrophy of adipose tissue and increase the risk of developing metabolic syndrome, including insulin resistance.

据报道，双酚 A (BPA) 用于各种与消费者相关的塑料产品，会引起不良影响，包括破坏脂肪细胞分化、干扰肥胖机制以及破坏胰岛素和葡萄糖稳态。替代化合物越来越多，但尚未得到充分研究。 我们旨在研究 BPA 及其四种替代品在人类前脂肪细胞向脂肪细胞分化过程中的作用模式，以及它们与过氧化物酶体增殖物激活受体 γ (PPARγ)（脂肪生成的关键调节剂）的分子相互作用。 分别通过表面等离子体共振和报告基因测定研究了 PPARγ 的结合和有效生物活化。人类前脂肪细胞持续暴露于 BPA、BPS、BPB、BPF、BPAF 和 PPARγ-拮抗剂 GW9662。分化 12 天后，通过油红 O 染色量化脂质产生，并使用基于 LC-MS/MS 的蛋白质组学评估全局蛋白质谱。所有测试的双酚都与人 PPARγ 结合，在体外具有与天然配体 15d-PGJ2 相似的功效  并在非细胞毒性浓度的报告基因测定中引起对 PPARγ 的拮抗作用。在人类前脂肪细胞的分化过程中，所有双酚都会降低脂质的产生。全球蛋白质组学显示出脂肪生成和代谢途径的下调，类似于 GW9662。有趣的是，促炎通路被上调，MCP1 释放增加，脂联素减少。pAKT/AKT 比率表明 BPA、BPB 和 BPS 在胰岛素刺激下显着降低了胰岛素敏感性。 因此，我们的结果表明，在与环境相关的低浓度下，BPA 及其替代品都会破坏脂肪细胞中关键的代谢功能和胰岛素信号传导。这种通过抑制 PPARγ 介导的效应可能会促进脂肪组织肥大并增加发生代谢综合征（包括胰岛素抵抗）的风险。