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.
MeSH terms
- AMP-Activated Protein Kinases
- Animals
- Biphenyl Compounds
- 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
- Biphenyl Compounds
- 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)
- 4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile