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

Authors
Journal
Cell Metabolism
1550-4131
Publisher
Elsevier
Publication Date
Volume
3
Issue
6
Identifiers
DOI: 10.1016/j.cmet.2006.05.005
Keywords
  • Signaling
Disciplines
  • Biology
  • Medicine

Abstract

Summary 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 (EC 50 = 0.8 μM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC 50 = 3.2 μM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl CoA levels and the respiratory exchange ratio, VCO 2/VO 2, 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.

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