The Role of Dietary Phytoestrogens and the Nuclear Receptor PPARγ in Adipogenesis: An in Vitro Study

BACKGROUND: Phytoestrogens, naturally occurring plant chemicals, have long been thought to confer beneficial effects on human cardiovascular and metabolic health. However, recent epidemiological studies, have yielded conflicting outcomes, in which phytoestrogen consumption was both positively and negatively correlated with adiposity. Interestingly, several dietary phytoestrogens are known to stimulate or inhibit the activity of the peroxisome proliferator-activated receptor gamma (PPAR gamma), a key physiological regulator of adipogenesis. OBJECTIVE: The objective of this study was to test the hypothesis that the pro- or anti-adipogenic activity of phytoestrogen chemicals is related to the ability to activate PPAR gamma in adipocytes. METHODS: The effects of resveratrol and the soy isoilavones genistein and daidzein on adipogenesis were examined in cell-based assays using the 3T3-L1 cell model. In parallel, ligand-mediated alterations in PPAR gamma target gene expression were measured by quantitative polymerase chain reaction. The agonist/antagonist activities of phytoestrogens on PPAR gamma were further assessed by quantifying their ability to affect recruitment of transcriptional cofactors to the receptor. RESULTS: Resvcratrol displayed significant anti-adipogenic activities as exhibited by the ability to antagonize PPAR gamma-dependent adipocyte differentiation, down-regulate genes involved in lipid metabolism, block cofactor recruitment to PPAR gamma, and antagonize the effects of the PPAR gamma agonist rosiglitazone. In contrast, genistein and daidzein functioned as PPAR gamma agonists while also displaying pro-adipogenic activities. CONCLUSIONS: These data provide biological evidence that the pro- or anti-obesity effects of phytoestrogens are related to their relative agonist/antagonist activity on PPAR gamma. Thus, PPAR gamma-activation assays may enable the screening of dietary components and identification of agents with adipogenic activities.