Emodin regulates glucose utilization by activating AMP-activated protein kinase

J Biol Chem. 2013 Feb 22;288(8):5732-42. doi: 10.1074/jbc.M112.441477. Epub 2013 Jan 9.

Abstract

AMP-activated protein kinase has been described as a key signaling protein that can regulate energy homeostasis. Here, we aimed to characterize novel AMP-activated kinase (AMPK)-activating compounds that have a much lower effective concentration than metformin. As a result, emodin, a natural anthraquinone derivative, was shown to stimulate AMPK activity in skeletal muscle and liver cells. Emodin enhanced GLUT4 translocation and [(14)C]glucose uptake into the myotube in an AMPK-dependent manner. Also, emodin inhibited glucose production by suppressing the expression of key gluconeogenic genes, such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, in hepatocytes. Furthermore, we found that emodin can activate AMPK by inhibiting mitochondrial respiratory complex I activity, leading to increased reactive oxygen species and Ca(2+)/calmodulin-dependent protein kinase kinase activity. Finally, we confirmed that a single dose administration of emodin significantly decreased the fasting plasma glucose levels and improved glucose tolerance in C57Bl/6J mice. Increased insulin sensitivity was also confirmed after daily injection of emodin for 8 days using an insulin tolerance test and insulin-stimulated PI3K phosphorylation in wild type and high fat diet-induced diabetic mouse models. Our study suggests that emodin regulates glucose homeostasis in vivo by AMPK activation and that this may represent a novel therapeutic principle in the treatment of type 2 diabetic models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Blood Glucose / metabolism
  • Calcium / metabolism
  • Cell Line
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Emodin / pharmacology*
  • Enzyme Activation
  • Gene Expression Regulation*
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Insulin Resistance
  • Liver / metabolism
  • Male
  • Mice
  • Models, Genetic
  • Muscle, Skeletal / cytology
  • Myoblasts / cytology

Substances

  • Blood Glucose
  • AMP-Activated Protein Kinases
  • Glucose
  • Emodin
  • Calcium