Catechin-induced activation of the LKB1/AMP-activated protein kinase pathway

Abstract

Catechins are abundant in green tea and induce a variety of biologic actions, including anti-cancer, anti-obesity, and anti-diabetes effects, and their clinical application has been widely investigated. To clarify the underlying molecular mechanisms of these actions, we examined the effect of catechins on AMP-activated protein kinase (AMPK) in cultured cells and in mice. In Hepa 1-6, L6, and 3T3-L1 cells, epigallocatechin gallate (EGCG) induced increases in AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC) phosphorylation, and AMPKalpha activity. Analysis of the molecular specificity of eight naturally occurring catechins revealed that catechins with a gallocatechin moiety or a galloyl residue act as AMPK activators. In addition, phosphorylation of LKB1, which is a tumor-suppressor protein and a major AMPK-kinase, was increased by catechin treatment. EGCG-induced phosphorylation of LKB1 and AMPKalpha was suppressed by treatment with catalase, suggesting that reactive oxygen species are involved in EGCG-induced activation of the LKB1/AMPK pathway. Oral administration of EGCG (200mg/kg body weight) to BALB/c mice induced an increase in AMPKalpha activity in the liver concomitant with a significant increase in AMPKalpha and ACC phosphorylation. EGCG administration also increased oxygen consumption and fat oxidation, as determined by indirect calorimetry. These findings suggest that multiple effects of catechins, including anti-obesity and anti-cancer effects, are mediated, at least in part, by the activation of LKB1/AMPK in various tissues, and that these effects vary according to the catechin structure.