In obese rodents, excess myocardial lipid accumulation (lipotoxicity) of 
myocardium may cause cardiomyopathy that in the obese Zucker diabetic fatty 
(ZDF) fa/fa rat can be prevented by treatment with troglitazone (TGZ). To 
determine the underlying mechanisms, we measured total 5'-AMP-activated kinase 
(AMPK) protein and its activated, phosphorylated form, P-AMPK. P-AMPK was 
significantly reduced in both ZDF fa/fa rat and ob/ob mouse hearts compared with 
lean, wild-type controls. TGZ treatment of obese ZDF rats, which lowered cardiac 
lipid content, increased P-AMPK. Expression of protein phosphatase 2C (PP2C), 
which inactivates AMPK activity by dephosphorylation, was increased in untreated 
ZDF fa/fa rat hearts, but fell with TGZ treatment, suggesting that PP2C can 
influence AMPK activity. In cultured myocardiocytes, fatty acids reduced P-AMPK, 
suggesting a feed-forward effect of lipid overload. Our findings highlight a 
role of PP2C and AMPK in the derangements of cardiac lipid metabolism in obesity 
and provide new insights as to the mechanisms of the liporegulatory disorder 
leading to lipotoxic cardiomyopathy.