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


CONCLUSIONS
Yhhu981 is a potent compound that stimulates fatty acid oxidation, and exerts pleiotropic effects on lipid metabolism by activating AMPK.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Hong-liang
HL
Zeng
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Su-ling
SL
Huang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Fu-chun
FC
Xie
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Li-min
LM
Zeng
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
You-hong
YH
Hu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Ying
Y
Leng
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008820:Mice, Obese; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000201:enzymology; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012118:Resorcinols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
D000480:Alkynes; D019440:Anti-Obesity Agents; D020536:Enzyme Activators; D005227:Fatty Acids; D047428:Protein Kinase Inhibitors; D012118:Resorcinols; C000603997:Yhhu981; D055372:AMP-Activated Protein Kinases; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase