Astaxanthin (ASX), an oxygenated
carotenoid (xanthophyll), has previously been shown to exert ameliorative effects on
obesity and
insulin resistance, but the underlying mechanisms were not clearly elucidated. In the present study, we investigated whether ASX serves as a novel selective
peroxisome proliferator-activated receptor (
PPAR) γ modulator. Analyses of PPARγ binding by
CoA-BAP assays revealed that ASX bound to PPARγ in a dose-dependent manner. However, ASX was unable to activate transcription in PPARγ reporter assays, although it antagonized transcriptional activation by the PPARγ agonist
rosiglitazone (RGZ). When the molecular interactions between PPARγ and three coactivators were examined, ASX increased the interactions of PPARγ with transcriptional intermediary factor 2 (TIF2) and
steroid receptor coactivator-1 (SRC-1), but not cAMP responsive
element-
binding protein (
CREB)-binding protein (CBP). In addition, ASX effectively blocked the increase in CBP recruitment to PPARγ mediated by RGZ. ASX alone did not stimulate 3T3-L1 cell differentiation, although it antagonized 3T3-L1 cell differentiation and
lipid accumulation induced by RGZ, similar to the PPARγ antagonist
GW9662. When the effects of cotreatment of 3T3-L1 cells with ASX and RGZ were determined based on the
mRNA levels of PPARγ target genes, ASX effectively reduced the
mRNA levels of aP2 and
lipoprotein lipase, but not CD36. Intriguingly, ASX was capable of inducing PPARγ target genes such as
liver X receptor, CD36 and ABCA1 in thioglycollate-elicited peritoneal macrophages. Collectively, the present findings indicate that ASX is a novel selective PPARγ modulator that acts as an antagonist or agonist depending on the cell context.