TY - JOUR
T1 - Therapeutic potential of panduratin A, LKB1-dependent AMP-activated protein kinase stimulator, with activation of PPARα/δ for the treatment of obesity
AU - Kim, D.
AU - Lee, M. S.
AU - Jo, K.
AU - Lee, K. E.
AU - Hwang, J. K.
PY - 2011/7
Y1 - 2011/7
N2 - Aim: AMP-activated protein kinase (AMPK) activators have shown potential as therapeutic agents for metabolic disorders. This study was conducted to evaluate therapeutic potential of panduratin (PAN) A, a natural AMPK stimulator, with activation of PPARα/δ for the treatment of obesity. Methods: We used the novel AMPK activator PAN A, a natural compound isolated from Boesenbergia pandurata rhizomes, to investigate the regulation of LKB1-dependent AMPK-PPARα/δ signalling by western blot, reporter gene assay and small interfering RNA knockdown analysis. In addition, the antiobesity effects of PAN A were evaluated in C57BL/6J mice with high-fat diet (HFD)-induced obesity. Results: PAN A stimulated AMPK signalling, induced nuclear translocation of the AMPKα2 subunit and activated PPARα/δ; LKB1, a kinase that lies upstream of AMPK, mediated these effects. PAN A stimulated the direct binding of the AMPKα2 subunit to PPARα/δ, but PPARδ activation required direct interaction with PPARγ coactivator 1α (PGC-1α). Further, PAN A (50 mg/kg/day) reduced weight gain, fat mass, fatty liver and improved serum lipid profiles in obese mice. Additionally, PAN A reduced ectopic fat accumulation and increased the proportion of slow-twitch myofibres and mitochondria content in skeletal muscle, thereby increasing running endurance. Conclusions: PAN A, an LKB1-dependent AMPK stimulator, activated PPARα/δ and attenuated HFD-induced obesity and dysregulation of lipid metabolism. Our findings suggest that PAN A is a potent AMPK activator and show a novel molecular mechanism for the treatment of metabolic disorders.
AB - Aim: AMP-activated protein kinase (AMPK) activators have shown potential as therapeutic agents for metabolic disorders. This study was conducted to evaluate therapeutic potential of panduratin (PAN) A, a natural AMPK stimulator, with activation of PPARα/δ for the treatment of obesity. Methods: We used the novel AMPK activator PAN A, a natural compound isolated from Boesenbergia pandurata rhizomes, to investigate the regulation of LKB1-dependent AMPK-PPARα/δ signalling by western blot, reporter gene assay and small interfering RNA knockdown analysis. In addition, the antiobesity effects of PAN A were evaluated in C57BL/6J mice with high-fat diet (HFD)-induced obesity. Results: PAN A stimulated AMPK signalling, induced nuclear translocation of the AMPKα2 subunit and activated PPARα/δ; LKB1, a kinase that lies upstream of AMPK, mediated these effects. PAN A stimulated the direct binding of the AMPKα2 subunit to PPARα/δ, but PPARδ activation required direct interaction with PPARγ coactivator 1α (PGC-1α). Further, PAN A (50 mg/kg/day) reduced weight gain, fat mass, fatty liver and improved serum lipid profiles in obese mice. Additionally, PAN A reduced ectopic fat accumulation and increased the proportion of slow-twitch myofibres and mitochondria content in skeletal muscle, thereby increasing running endurance. Conclusions: PAN A, an LKB1-dependent AMPK stimulator, activated PPARα/δ and attenuated HFD-induced obesity and dysregulation of lipid metabolism. Our findings suggest that PAN A is a potent AMPK activator and show a novel molecular mechanism for the treatment of metabolic disorders.
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U2 - 10.1111/j.1463-1326.2011.01379.x
DO - 10.1111/j.1463-1326.2011.01379.x
M3 - Article
C2 - 21320266
AN - SCOPUS:79956320223
SN - 1462-8902
VL - 13
SP - 584
EP - 593
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
IS - 7
ER -
