Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice

Abstract

Aims/hypothesis Arctigenin is a natural compound that had never been previously demonstrated to have a glucoselowering effect. Here it was found to activate AMPactivated protein kinase (AMPK), and the mechanism by which this occurred, as well as the effects on glucose and lipid metabolism were investigated. Methods 2-Deoxyglucose uptake and AMPK phosphorylation were examined in L6 myotubes and isolated skeletal muscle. Gluconeogenesis and lipid synthesis were evaluated in rat primary hepatocytes. The acute and chronic effects of arctigenin on metabolic abnormalities were observed in C57BL/6J and ob/ob mice. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye, JC-1. Analysis of respiration of L6 myotubes or isolated mitochondria was conducted in a channel oxygen system. Results Arctigenin increased AMPK phosphorylation and stimulated glucose uptake in L6 myotubes and isolated skeletal muscles. In primary hepatocytes, it decreased gluconeogenesis and lipid synthesis. The enhancement of glucose uptake and suppression of hepatic gluconeogenesis and lipid synthesis by arctigenin were prevented by blockade of AMPK activation. The respiration of L6 myotubes or isolated mitochondria was inhibited by arctigenin with a specific effect on respiratory complex I. A single oral dose of arctigenin reduced gluconeogenesis in C57BL/6J mice. Chronic oral administration of arctigenin lowered blood glucose and improved lipid metabolism in ob/ob mice. Conclusions/interpretation This study demonstrates a new role for arctigenin as a potent indirect activator of AMPK via inhibition of respiratory complex I, with beneficial effects on metabolic disorders in ob/ob mice. This highlights the potential value of arctigenin as a possible treatment of type 2 diabetes.

Arctigenin Protects Focal Cerebral Ischemia-Reperfusion Rats through Inhibiting Neuroinflammation

“…13,14) Previous studies reported that arctigenin ameliorated metabolic disorders via inhibition of mitochondria complex I. 15) Most recently, arctigenin was reported to confer neuroprotective effect via inhibition of neuroinflammation. 16) However, the anti-inflammatory effect of arctigenin against ischemic stroke has not been examined.…”

New expectations from the well-known medicinal properties of Arctium lappa

“…Thus, the hypothesis that arctigenin research may lead to the identification of agents mimicking the beneficial effects of exercise on metabolic disorders is not a new concept. However, the report by Huang et al [11] is the first to show a positive effect of arctigenin administration on glucose tolerance and lipid profile in mice. This advance is limited by the lack of in-depth investigation of the mechanisms responsible for the effects of arctigenin.…”

“…However, Huang and co-workers [11] found that this mechanism does not occur in the L6 muscle cell line. Instead, arctigenin-induced activation of AMPK occurs indirectly and is not dependent upon LKB1, CaMKK or the nitric oxide synthase cascades.…”

“…In addition, they show that arctigenin stimulates glucose uptake in cultured L6 skeletal muscle cells and isolated muscles, while inhibiting gluconeogenesis and lipid synthesis in primary hepatocytes [11]. Interestingly, all of these effects were blocked by AMPKα1/α2 silencing or pharmacological inhibition of AMPK, whereas pharmacological inhibition of phosphoinositide-3 kinase had no effect.…”

“…In this issue of Diabetologia, Huang et al [11] report that the natural dibenzylbutyrolactone-type lignanolide arctigenin, a molecule extracted from the traditional herb Arctium lappa L. (Compositae) that has previously been shown to feature anti-tumour and anti-inflammatory effects [12,13], increases AMPK phosphorylation. In addition, they show that arctigenin stimulates glucose uptake in cultured L6 skeletal muscle cells and isolated muscles, while inhibiting gluconeogenesis and lipid synthesis in primary hepatocytes [11].…”