Decreased phosphorylation in the
insulin signalling pathway is a hallmark of
insulin resistance. The causes of this phenomenon are complicated and multifactorial. Recently, genomic analyses have identified ARL15 as a new candidate gene related to diabetes. However, the ARL15
protein function remains unclear. Here, we show that ARL15 is upregulated by
insulin stimulation. This effect was impaired in
insulin-resistant pathophysiology in TNF-α-treated C2C12 myotubes and in the skeletal muscles of
leptin knockout mice. In addition, ARL15 localized to the cytoplasm in the resting state and accumulated in the Golgi apparatus around the nucleus upon
insulin stimulation. ARL15 overexpression can enhance the phosphorylation of the key
insulin signalling pathway molecules IR, IRS1 and AKT in C2C12 myotubes. Moreover, ARL15 knockdown can also specifically inhibit the phosphorylation of PDPK1 Ser241, thereby reducing PDPK1 activity and its downstream phosphorylation of AKT Thr308. Co-immunoprecipitation assays identified ASAP2 as an ARL15-interacting
protein. In conclusion, we have identified that ARL15 acts as an
insulin-sensitizing effector molecule to upregulate the phosphorylation of members of the canonical IR/IRS1/PDPK1/AKT
insulin pathway by interacting with its GAP ASAP2 and activating PDPK1. This research may provide new insights into
GTPase-mediated
insulin signalling regulation and facilitate the development of new pharmacotherapeutic targets for
insulin sensitization.