Yhhu981, a novel compound, stimulates fatty acid oxidation via the activation of AMPK and ameliorates lipid metabolism disorder in ob/ob mice

Acta Pharmacol Sin. 2015 Mar;36(3):343-52. doi: 10.1038/aps.2014.147.


Aim: Defects in fatty acid metabolism contribute to the pathogenesis of insulin resistance and obesity. In this study, we investigated the effects of a novel compound yhhu981 on fatty acid metabolism in vitro and in vivo.

Methods: The capacity to stimulate fatty acid oxidation was assessed in C2C12 myotubes. The fatty acid synthesis was studied in HepG2 cells using isotope tracing. The phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) was examined with Western blot analysis. For in vivo experiments, ob/ob mice were orally treated with yhhu981 acutely (300 mg/kg) or chronically (150 or 300 mg·kg(-1)·d(-1) for 22 d). On the last day of treatment, serum and tissue samples were collected for analysis.

Results: Yhhu981 (12.5-25 μmol/L) significantly increased fatty acid oxidation and the expression of related genes (Sirt1, Pgc1α and Mcad) in C2C12 myotubes, and inhibited fatty acid synthesis in HepG2 cells. Furthermore, yhhu981 dose-dependently increased the phosphorylation of AMPK and ACC in both C2C12 myotubes and HepG2 cells. Compound C, an AMPK inhibitor, blocked fatty acid oxidation in yhhu981-treated C2C12 myotubes and fatty acid synthesis decrease in yhhu981-treated HepG2 cells. Acute administration of yhhu981 decreased the respiratory exchange ratio in ob/ob mice, whereas chronic treatment with yhhu981 ameliorated the lipid abnormalities and ectopic lipid deposition in skeletal muscle and liver of ob/ob mice.

Conclusion: Yhhu981 is a potent compound that stimulates fatty acid oxidation, and exerts pleiotropic effects on lipid metabolism by activating AMPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / metabolism*
  • Acetyl-CoA Carboxylase / metabolism
  • Alkynes / pharmacology*
  • Animals
  • Anti-Obesity Agents / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Energy Metabolism / drug effects
  • Enzyme Activation
  • Enzyme Activators / pharmacology*
  • Fatty Acids / metabolism*
  • Hep G2 Cells
  • Humans
  • Liver / drug effects*
  • Liver / enzymology
  • Mice, Obese
  • Muscle Fibers, Skeletal / drug effects*
  • Muscle Fibers, Skeletal / enzymology
  • Obesity / drug therapy*
  • Obesity / enzymology
  • Oxidation-Reduction
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Resorcinols / pharmacology*
  • Signal Transduction / drug effects
  • Up-Regulation


  • Alkynes
  • Anti-Obesity Agents
  • Enzyme Activators
  • Fatty Acids
  • Protein Kinase Inhibitors
  • Resorcinols
  • Yhhu981
  • AMP-Activated Protein Kinases
  • ACACA protein, human
  • Acetyl-CoA Carboxylase