Abstract
AMP-activated protein kinase (AMPK) is a key sensor and regulator of glucose metabolism. Here, we demonstrated that shizukaol F, a natural compound isolated from Chloranthus japonicus, can activate AMPK and modulate glucose metabolism both in vitro and in vivo. Shizukaol F increased glucose uptake in differentiated C2C12 myotubes by stimulating glucose transporter-4 (GLUT-4) membraned translocation. Treatment of primary mouse hepatocytes with shizukaol F decreased the expression of phosphoenolpyruvate carboxykinase 2 (PEPCK), glucose-6-phosphatase (G6Pase) and suppressed hepatic gluconeogenesis. Meanwhile, a single oral dose of shizukaol F reduced gluconeogenesis in C57BL/6 J mice. Further studies indicated that shizukaol F modulates glucose metabolism mainly by AMPKa phosphorylation activity. In addition, we also found that shizukaol F depolarizes the mitochondrial membrane and inhibits respiratory complex I, which may result in AMPK activation. Our results highlight the potential value of shizukaol F as a possible treatment of metabolic syndrome.
Highlights
AMP-activated kinase (AMPK) is widely recognized as an efficient sensor of intracellular and whole-body energy metabolism
AMPK activation suppresses the expression of two key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase 2 (PEPCK) and glucose-6-phosphatase (G6Pase)
Our results showed that shizukaol F activated AMPK, increased the glucose uptake in skeletal muscle cells and reduced gluconeogenesis both in primary hepatic cells and in vivo via an AMPKa phosphorylation dependent mechanism
Summary
AMP-activated kinase (AMPK) is widely recognized as an efficient sensor of intracellular and whole-body energy metabolism It is a heterotrimeric serine/threonine kinase that regulates fatty acid and glucose homeostasis, and can be used as an attractive target for the treatment of these related disorders[1]. Leptin activates AMPK to increase fatty acid oxidation in skeletal muscle and hepatocytes, while adiponectin, previously identified as a key regulator of lipid and glucose metabolism, stimulates AMPK activity in several types of tissues[2]. Our results showed that shizukaol F activated AMPK, increased the glucose uptake in skeletal muscle cells and reduced gluconeogenesis both in primary hepatic cells and in vivo via an AMPKa phosphorylation dependent mechanism. Further results showed that the activation of AMPK by shizukaol F is caused by inhibition of mitochondrial complex I activity
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