panduratin-a and Obesity

Obesity is not only viewed as a chronic aggressive disorder but is also associated with an increased risk for various diseases. Nonetheless, new anti-obesity drugs are an urgent need since few pharmacological choices are available on the market. Natural compounds have served as templates for drug discovery, whereas modified molecules from the leads identified based on in vitro models often reveal noncorresponding bioactivity between in vitro and in vivo studies. Therefore, to provide inspiration for the exploration of innovative anti-obesity agents, recent discoveries of natural anti-obesity compounds with in vivo evidence have been summarized according to their chemical structures, and the comparable efficacy of these compounds is categorized using animal models. In addition, several synthetic derivatives optimized from the phytochemicals are also provided to discuss medicinal chemistry achievements guided by natural sources.

Topics: Animals; Anti-Obesity Agents; Drug Discovery; Obesity; Phytochemicals

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.. 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.. 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.. 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.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; Blotting, Western; Chalcones; Drug Evaluation, Preclinical; Gene Knockdown Techniques; Male; Mice; Mice, Inbred C57BL; Obesity; PPAR alpha; Protein Serine-Threonine Kinases; Signal Transduction