Activation of SIK1 by phanginin A regulates skeletal muscle glucose uptake by phosphorylating HADC4/5/7 and enhancing GLUT4 expression and translocation

Salt-inducible kinase 1 (SIK1) participates in various physiological processes, yet its involvement in regulating skeletal muscle glucose uptake remains unclear. Previously, we showed that phanginin A, a natural compound isolated from Caesalpinia sappan Linn, activated SIK1 to suppress gluconeogenesis in hepatocytes. Here, we aimed to elucidate the effects of SIK1 on skeletal muscle glucose uptake by using phanginin A. The C2C12 myotubes were incubated with phanginin A and then glucose uptake, mRNA levels, membrane GLUT4 content, phosphorylation levels of proteins in SIK1/HDACs and Akt/AS160 signaling pathways were determined. Phanginin A significantly promoted glucose uptake, while the pan-SIK inhibitor or knocking down SIK1 expression abolished the promotion. Further exploration showed that phanginin A enhanced GLUT4 mRNA levels by increasing histone deacetylase (HDAC) 4/5 phosphorylation and MEF2a mRNA and protein level, and knocking down SIK1 blocked these effects. Additionally, phanginin A induced HDAC7 phosphorylation, upregulated the junction plakoglobin (JUP) expression and Akt/AS160 phosphorylation. Knocking down JUP or SIK1 both attenuated the phanginin A-induced Akt/AS160 signaling and glucose uptake, suggesting that activation of SIK1 by phanginin A inactivated HDAC7 to increase JUP expression and Akt/AS160 phosphorylation, led to upregulation of GLUT4 translocation and glucose uptake. In vivo study showed that phanginin A increased phosphorylation levels of SIK1, HDAC4/5/7, Akt/AS160, and gene expression of MEF2a, GLUT4 and JUP, accompanied by elevated membrane GLUT4 and glycogen content in gastrocnemius muscle of C57BL/6 J mice, indicating enhanced glucose utilization. These findings reveal a novel mechanism that SIK1 activation by phanginin A stimulates skeletal muscle glucose uptake through phosphorylating HADC4/5/7 and the subsequent enhancement of GLUT4 expression and translocation.