WSF-CT-11, a Sesquiterpene Derivative, Activates AMP-Activated Protein Kinase with Anti-diabetic Effects in 3T3-L1 Adipocytes

Background: AMP-activated protein kinase (AMPK) is a therapeutic target against type II diabetes (T2D). Synthetic sesquiterpene derivatives were investigated to identify novel AMPK activators as anti-diabetic drugs because the leading drugs like metformin and thiazolidinediones (TZDs) activate AMPK by inhibiting the synthesis of adenosine 5'-triphosphate and thus are associated with some side effects. Results: We identified WSF-CT-11 as an AMPK activator in HEK293T cells and found that WSF-CT-11 activates AMPK by the activation of transient receptor potential vanilloid type 1 (TRPV1), a Ca2+-permeable cation channel. The increased Ca2+ influx then activates phosphoinositide 3-kinase (PI3K), protein kinase B (PKB/Akt), and Ca2+/calmodulin-dependent protein kinase II (CaMKII), which in turn phosphorylates TRPV1 and facilitates the formation of a TRPV1/Akt/CaMKII/AMPK complex. This complex might be important for the regulation of AMPK activity. In 3T3-L1 adipocytes, WSF-CT-11-induced AMPK activation has three anti-diabetic effects. It promotes the assembly of high-molecular-weight adiponectin, which has stronger insulin-sensitizing activity than other multimers. It improves translocation of the glucose transporter type 4, increases glucose uptake, and induces the inhibitory phosphorylation of peroxisome proliferator-activated receptor. and thus suppresses adipogenesis. Conclusion: WSF-CT-11 is a novel AMPK activator and potential drug against T2D without the side effects of metformin and TZDs.