Combretastatin A-4 activates AMP-activated protein kinase and improves glucose metabolism in db/db mice.
Resveratrol was reported to increase insulin sensitivity accompanied with the activation of AMP-activated protein kinase (AMPK), which is a key regulator of energy balance and an important drug target for type 2 diabetes. However, the effect of resveratrol structural analogs on AMPK activity and insulin sensitivity is still largely unknown. In this study, we analyzed the effect of several resveratrol structural analogs on AMPK activity in HepG2 cells, and combretastatin A-4 (CA-4) was identified as an activator of AMPK determined by its phosphorylation. AMPK activation was further confirmed by the phosphorylation of downstream acetyl-CoA carboxylase (ACC) and the decrease of upstream ATP level. Further investigation showed that CA-4 activates PPAR transcriptional activity in vitro with the luciferase reporter assay. In addition, we showed that CA-4 activated AMPK and downregulated gluconeogenic enzyme mRNA levels in liver, and improved the fasting blood glucose level in diabetic db/db mice. These results suggested that resveratrol analogs, such as CA-4, can function similarly as resveratrol and may provide important tools for improving insulin sensitivity.
Zhang
Fang
F
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, PR China.
Sun
Cheng
C
Wu
Jingxia
J
He
Chunyan
C
Ge
Xinjian
X
Huang
Wenming
W
Zou
Yong
Y
Chen
Xingmiao
X
Qi
Wei
W
Zhai
Qiwei
Q
D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
D009097:Multienzyme Complexes; D013267:Stilbenes; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; C058728:fosbretabulin; D005947:Glucose