Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.

Dedifferentiated fat (DFAT) cells are adipocyte-derived cells that are able to differentiate into multiple cell lineages such as adipocytes, osteoblasts and chondrocytes, similar to mesenchymal stem cells (MSCs). Despite their great potential for developing novel clinical interventions by using their multipotency, the detailed mechanisms of how adipocytes undergo dedifferentiation into DFAT cells are not completely understood, because useful in vitro tools for studying adipocyte dedifferentiation are missing. In this study, we show that mature adipocytes derived from the MSC cell line C3H10T1/2 underwent dedifferentiation into cells with DFAT cell-like characteristics, when they were cultured in an inverted flask. During the dedifferentiation, expression levels of genes and protein specific to adipocytes were continuously decreased, whereas those for MSC, proliferation and WNT/β-catenin signaling were gradually increased. These DFAT-like cells also underwent differentiation into adipocytes, osteoblasts and chondrocytes with their specific cell morphology and gene expression. We also observed that an individually cultured single adipocyte also underwent dedifferentiation into DFAT-like cells that were able to differentiate into the multiple cell lineages. Our results indicate that C3H10T1/2 cells could be a great tool for determining molecular biological and biochemical mechanisms underlying adipocyte dedifferentiation.