Key result
Troglitazone reduces cardiac lipids and restores AMPK signaling in obese rat models of lipotoxic cardiomyopathy.
Why the study?
Excess myocardial lipid accumulation in obese rodents may cause cardiomyopathy, and the mechanisms underlying its prevention by troglitazone are unclear.
Does troglitazone treatment prevent cardiac lipid accumulation and modulate AMPK/PP2C activity in obese rodents?
Does troglitazone treatment prevent cardiac lipid accumulation and modulate AMPK/PP2C activity in obese rodents?
Troglitazone prevents lipotoxic cardiomyopathy in obese rodents by modulating the PP2C-AMPK pathway, highlighting a potential mechanism for managing cardiac lipid metabolism.
Reduced P-AMPK in obese rodent hearts; leaves open AMPK-targeted prevention of lipotoxic cardiomyopathy in humans.
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.
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Wang et al. (2004) studied Cardiac lipid accumulation (lipotoxicity) and cardiomyopathy in obesity. Troglitazone (TGZ) vs. Untreated obese rodents and lean, wild-type controls was evaluated on P-AMPK levels and PP2C expression. Troglitazone treatment in obese ZDF rats lowered cardiac lipid content, increased P-AMPK, and reduced PP2C expression, highlighting their role in obesity-related lipotoxic cardiomyopathy.
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