5-(3, 4-Dihydroxyphenyl)-γ-valerolactone, a Metabolite of Procyanidins in Cacao, Suppresses MDI-induced Adipogenesis by Regulating Cell Cycle Progression

Abstract

Cacao (Theobroma cacao) which includes a large amount of polyphenols, has been reported to have potent beneficial effects on obesity. However, all of these previous studies have focused on the extract form of cacao or procyanidins and their potential mechanisms have not been fully elucidated with considering ADME (absorption, distribution, metabolism, and excretion). Here, in this study, I investigated the inhibitory effects of metabolites of procyanidins on adipogenic cocktail (MDI)-induced adipogenesis and lipogenesis in 3T3-L1 preadipocytes. Especially, 5-(3, 4-Dihydroxyphenyl)-γ-valerolactone (DHPV) which is known for the major metabolite of proycanidins, had the best inhibitory effects on adipogenesis and lipogenesis. I found that DHPV decreased the protein expression levels which are involved in adipogenesis such as peroxisome proliferator-activated receptor γ (PPAR γ) and CCAT/enhancer-binding protein α (C/EBP α), and lipogenesis such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) dose-dependently. These inhibitory effects were mainly due to G1 phase arrest in the early stage of adipogenesis which called as mitotic clonal expansion (MCE) by suppressing cell proliferation. In kinase array, CDK2/cyclin O was preferentially selected through several citeria. DHPV directly suppressed activation of CDK2/cyclin O complex. DHPV inhibited the phosphorylation of C/EBP β which is responsible for induction of PPAR γ and C/EBP α. Taken together, this study implied that DHPV is one of the biologically active compound of cacao which brings the potential benefits on anti-obesity by inhibiting intracellular lipid contents and cell differentiation.