The
effects of three B-type proanthocyanidin (PA) dimers covering
procyanidin B2 (B-0g), procyanidin B2 3′-O-gallate (B-1g),
and procyanidin B2 3,3′-di-O-gallate (B-2g) on 3T3-L1 preadipocyte
differentiation and the underlying mechanisms were investigated. The
results showed that digalloylated B-type PA dimers (B-2g) strongly
inhibited 3T3-L1 preadipocyte differentiation through disrupting the
integrity of the lipid raft structure and inhibiting the expression
of peroxisome proliferator-activated receptor gamma (PPARγ)
and CCAAT/enhancer-binding protein alpha (C/EBPα) and then downregulating
the expression of acetyl-CoA carboxylase (ACC) and fatty acid synthase
(FAS) factors, followed by B-1g, while B-0g had little effect. The
different inhibitory effects were mainly due to the difference in
the B-type PA dimer structure and the ability to interfere with lipid
rafts. The greater the galloylation degree of B-type PA dimers, the
stronger the ability to disrupt the lipid raft structure and oppose
3T3-L1 preadipocyte differentiation. In addition, galloylated B-type
PA dimers had greater molecular hydrophobicity and topological polarity
surface area and could penetrate into the lipid rafts to form multiple
hydrogen bonds with the rafts by molecular dynamics simulation. These
findings highlighted that the strong lipid raft-perturbing potency
of galloylated B-type PA dimers was responsible for inhibition of
3T3-L1 preadipocyte differentiation.
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 ultrahighresolution 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.