Central relaxin-3/RXFP3 signaling potently drives orexigenic behaviors and attenuates cisplatin-induced anorexia and body weight loss.

The relaxin-3 neuropeptide system promotes energy balance by increasing feeding behavior. Here, we investigate the behavioral mechanisms mediating the orexigenic effects of relaxin-3 and the therapeutic potential of relaxin-3 to combat metabolic disorders. We show that central and peripheral administration of relaxin-3 increases high-fat diet intake by increasing meal size in obese rats. Furthermore, we deleted relaxin family peptide receptor 3 (RXFP3) neuronally using RXFP3 fl/fl hSyn-Cre+ mice and show that neuronal RXFP3 is required for the orexigenic effects of relaxin-3. In addition, central relaxin-3 administration augmented food motivation for sucrose and hyperphagia in a binge-like eating model. We then evaluated the potential of relaxin-3 to drive food intake in rats receiving acute maladaptive chemotherapy. Pretreatment of central relaxin-3 attenuated cisplatin chemotherapy-induced anorexia and body weight loss. These findings characterize the behavioral mechanisms by which the relaxin-3 system drives feeding behaviors and highlight its therapeutic potential for metabolic wasting disorders.