TAS1R3 biases bone marrow stromal cell fate toward adipogenesis through PLCβ4-p38 signaling

How mesenchymal lineage allocation is regulated by nutrients remains poorly understood. Here, we identify TAS1R3, which has been recognized as a component of taste receptors in the taste buds, as being expressed in bone marrow stromal cells (BMSCs) and as a regulator of BMSC fate. Genetic deletion or pharmacological inhibition of TAS1R3 impaired adipogenic differentiation in primary BMSCs, whereas TAS1R3 overexpression enhanced adipogenesis in a BMSC-derived cell line. Consistent results were observed in a human MSC model, in which TAS1R3 promoted adipogenic differentiation and suppressed osteogenic differentiation. Transcriptomic, pharmacological, and knockdown analyses showed that TAS1R3 promotes adipogenesis through phospholipase C beta 4 (PLCβ4)-dependent p38 mitogen-activated protein kinase (MAPK) activation. In contrast, under osteogenic conditions, TAS1R3 attenuated p38 phosphorylation, reduced alkaline phosphatase activity, and restrained osteogenic differentiation. Together, these findings identify TAS1R3 as a context-dependent regulator of p38 signaling and show that extraoral TAS1R3 signaling directs mesenchymal lineage allocation toward adipogenesis at the expense of osteogenesis.