Target identification research on the adiponectin-secreting activity of kojyl cinnamate derivatives in human mesenchymal stem cells

Abstract

Human mesenchymal stem cells (hMSCs) possess the capacity for multi-lineage differentiation. Under the appropriate conditions, hMSCs can undergo cell fate decision to commit to adipogenic, osteogenic, chondrogenic, or myogenic lineages. In this regard, the adipogenesis of human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) can be used as a model for phenotype-based screening of anti-aging skin compounds with lipofilling effects. The kojyl cinnamate derivative, Seletinoid G, has been clinically proven to have anti-aging effects in human skin. However, the efficacy in the phenotype assay was not sufficient to perform molecular target identification research. In this study, we developed novel kojyl cinnamate derivatives for improved adiponectin promoting activity in hAT-MSCs. Through target deconvolution, we found that the adiponectin-secreting activities of kojyl cinnamates were correlated with PPARγ and PPARα, but not PPARδ activation. In a further investigation, we found that kojyl cinnamates with high binding affinities towards PPARγ and PPARα significantly increased the expressions of cholesterol and fatty acid synthesizing enzymes in both hAT-MSCs and primary normal human keratinocytes (NHKs). Our findings suggest that kojyl cinnamate derivatives with PPARγ and PPARα dual agonism have the potential to repair altered skin barrier function and improve aged-related decrease of subcutaneous adipose tissue.