Our previous investigation found that exendin4 (Ex4), a peptide analogue of glucagonlike peptide 1(GLP1), induced bone formation probably by osteoblast activation.Nevertheless, previous investigations did not observe any expression of GLP1 receptors in osteoblasts, indicating that the direct cell target of GLP1 and its analogues might not be osteoblasts but some other types of cells yet to be identified.To elucidate the underlying mechanisms, we performed further investigation in the present study and found that GLP1 receptor was only identified in bone marrow mesenchymal stem cells (BMSCs).Furthermore, activation of GLP1 receptor by Ex4 promoted the differentiation of BMSCs into osteoblast, which was associated with activation of PKA, nuclear translocation of 1βcatenin, activation of PI3K/AKT and inhibition of GSK3β.Ex4 also inhibited the adipocyte differentiation of BMSCs, as evidenced by inhibition of PPARγ, lipoprotein lipase expression and lipid production.Blockade of GLP1receptor, PKA, PI3K or Wnt pathway, or respective knockdown of GLP1 receptor and βcatenin in BMSCs inhibited the Ex4 mediated effects.The results indicated that the GLP1 receptor mediated osteoblastic differentiation and bone formation through stimulation of PKA/βcatenin signaling and inhibition of PKA/PI3K/AKT/GSK3β?signaling pathway in BMSCs.The findings reveal a new role of GLP1 receptor for regulating osteoblastic differentiation of BMSCs and may provide a molecular basis for novel anabolic therapeutics against osteoporosis.