RLN3/RXFP3 signaling in the PVN inhibits magnocellular neurons via M-like current activation and contributes to binge eating behavior

Binge-eating disorder (BED) is the most common eating disorder. Various neuropeptides play important role in the regulation of feeding behavior, including relaxin-3 (RLN3), which stimulates food intake through the activation of relaxin-family peptide 3 receptor (RXFP3). We demonstrated that the likely mechanism underlying RLN3 orexigenic action involves RXFP3-mediated inhibition of oxytocin- and arginine-vasopressin-synthesizing PVN magnocellular neurosecretory cells. Moreover, we showed that, regardless of sex, this action depends on M-like potassium conductance. Notably, higher intra- and peri-PVN RLN3 fiber densities were observed in females, which may constitute an anatomical substrate for sex differences in BED. Finally, in a rat model of binge-eating, RXFP3 blockage within the PVN in female rats prevented binge-eating behavior. These data identified a direct RLN3/RXFP3 action in the PVN of male and female rats together with the associated ionic mechanisms and revealed that hypothalamic RLN3/RXFP3 signaling regulates binge-eating behavior.