Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome

Cell Metab. 2006 Jun;3(6):403-16. doi: 10.1016/j.cmet.2006.05.005.

Abstract

AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metabolism. We have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 microM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 microM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl CoA levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body weight gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small molecule-mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.

Publication types

  • Comparative Study

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Cell Line
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Activators / chemistry*
  • Enzyme Activators / pharmacology
  • Enzyme Activators / therapeutic use*
  • Fatty Acid Synthases / drug effects
  • Fatty Acid Synthases / genetics
  • Fatty Acid Synthases / metabolism
  • Glucose-6-Phosphatase / drug effects
  • Glucose-6-Phosphatase / genetics
  • Glucose-6-Phosphatase / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • In Vitro Techniques
  • Metabolic Syndrome / drug therapy*
  • Metabolic Syndrome / metabolism
  • Metformin / chemistry
  • Metformin / pharmacology
  • Metformin / therapeutic use
  • Mice
  • Mice, Obese
  • Molecular Weight
  • Multienzyme Complexes / drug effects
  • Multienzyme Complexes / metabolism*
  • Phosphoenolpyruvate Carboxykinase (GTP) / drug effects
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Phosphoenolpyruvate Carboxykinase (GTP) / metabolism
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyrones / chemistry*
  • Pyrones / pharmacology
  • Pyrones / therapeutic use*
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology
  • Thiophenes / therapeutic use*

Substances

  • A 769662
  • Enzyme Activators
  • Multienzyme Complexes
  • Pyrones
  • RNA, Messenger
  • Thiophenes
  • Metformin
  • Fatty Acid Synthases
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Glucose-6-Phosphatase
  • Phosphoenolpyruvate Carboxykinase (GTP)