The prolactin-releasing peptide system: Physiological functions and therapeutic potential in obesity

Prolactin-releasing peptide (PrRP), an RF-amide neuropeptide, is now recognized as an important regulator of food intake and body weight. This review summarizes current knowledge regarding the physiological roles of PrRP, its receptors prolactin-releasing peptide receptor (PRLHR/GPR10) and neuropeptide FF receptor 2 (NPFFR2/GPR74), and the therapeutic potential of PrRP analogs in obesity treatment. Experimental studies using PrRP-, GPR10-, and NPFFR2-knockout mouse models have demonstrated that disruption of PrRP signaling markedly affects energy homeostasis. PrRP- and GPR10-deficient mice generally develop increased body weight, hyperphagia, adiposity and impaired glucose homeostasis, whereas NPFFR2-knockout models exhibit more complex, sex- and diet-dependent metabolic phenotypes. Moreover, the first characterization of double GPR10/NPFFR2 knockout mice revealed severe late-onset obesity accompanied by profound metabolic disturbances. Current evidence further suggests that, although GPR10 is the primary receptor for PrRP, several lipidized PrRP analogs exhibit increased affinity for NPFF receptors, particularly NPFFR2, and may also interact with additional receptor systems. Experimental studies further indicate that the anti-obesity effects of PrRP analogs are mediated through the coordinated action of GPR10 and NPFFR2 signaling pathways. Recent advances in the development of lipidized and stabilized PrRP analogs have demonstrated promising anti-obesity effects in preclinical mouse models. Several analogs have shown prolonged efficacy with limited weight regain following treatment withdrawal. Together, these findings identify the PrRP system as a promising target for the development of novel therapies for obesity and related metabolic disorders.