Targeting Lipid Rafts as a Rapid Screening Strategy for Potential Antiadipogenic Polyphenols along with the Structure–Activity Relationship and Mechanism Elucidation

Obesity is a global public health problem that endangers human health, and a rapid search for compounds with antiadipogenic activity could provide solutions to overcome this problem. Polyphenols are potential antiadipogenic compounds, but the screening strategy, structure-activity relationship (SAR), and elucidation of their mechanisms of action remain poorly understood because of the high diversity of polyphenols. Lipid rafts, enriched with sphingolipids and cholesterol, are considered a potential target of polyphenols for the regulation of cellular processes and diseases. Here, a novel rapid screening active polyphenol strategy that targets the lipid rafts using molecular dynamic simulation was developed and validated by 3T3-L1 preadipocyte assay. The screening strategy is high-throughput, inexpensive, reagent-free, and effort saving. In addition, the SAR and mechanisms of action mediating the differentiation-inhibition of the preadipocyte by polyphenols were well elucidated by utilizing multiple technologies, such as "raft-like liposomes" systems, giant plasma membrane vesicles, noninvasive lipid raft probes, and ultrahigh-resolution microscopy. High inhibitory-activity polyphenols could penetrate deeper into the hydrophobic lipid center, in an inverted V-shaped manner or by insertion of galloyl groups into rafts, thus disrupting the ordered domain of lipid rafts. In contrast, the medium and low inhibitory-activity polyphenols could only localize on the surface of lipid rafts, exerting slight and the weakest interference with a lipid raft structure, respectively. The combined use of reliable technologies could yield new knowledge on the SAR and the molecular mechanisms of polyphenols.