A small-molecule lycorine derivative reveals Na+/K+-ATPase α3 as an anti-obesity target

Abstract

AbstractObesity poses a global public health challenge and there is a huge unmet medical need for effective and safe anti-obesity therapeutics. Here, we discovered a small-molecule lycorine derivative designated as HLY72 that could potently promote lipolysis and reduce body weight in mice. Further study revealed that Na+/K+-ATPase α3 is the target of HLY72, and the Na+/K+-ATPase inhibitor digitoxin, but not istaroxime which could not go through blood-brain barrier, exhibits similar activities of reducing food intake and promoting lipolysis as HLY72 does in mice. Consistent with these findings, in knockin mice with a digitoxin-binding mutation T807C in Na+/K+-ATPase α3, but not in α1 gene, both digitoxin and HLY72 lose their activities. Furthermore, either chemical inhibition by HLY72 or genetic inhibition by T807C mutation of Na+/K+-ATPase α3 could effectively protect mice from diet-induced obesity. Therefore, we uncovered a previously unknown function of Na+/K+-ATPase α3 in the regulation of lipolysis and energy balance; and revealed a potential treatment and prevention strategy for obesity by targeting Na+/K+-ATPase α3.