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Anorexigenic neuropeptides have the potential to decrease food intake and ameliorate obesity and its complications such as high blood glucose or high blood pressure. However, they are not able to cross the blood-brain barrier after peripheral application. Recently, we have designed and synthesized lipidized analogs of prolactin-releasing peptide (PrRP), which resulted in stabilization of the molecule and allowed us to apply the peptide to the periphery to achieve its central biological effect, as it was demonstrated by increased neuronal activity shown by c-Fos in particular hypothalamus nuclei. The aim of this study was to choose the effective dose in acute food intake experiments and then to characterize the subchronic effect of palmitoylated PrRP analogs in mouse and rat models of obesity and diabetes. Several animal models were used: diet-induced obese (DIO) mice (C57Bl/6J), DIO Sprague-Dawley rats, and two rat models with leptin receptor-deficiency: Zucker diabetic (ZDF) rats and spontaneously hypertensive (SHROB) rats. Consumption of a high-fat diet in DIO mice and rats increased their body weight and blood pressure. Two-week intraperitoneal treatment with palmitoylated PrRP31 lowered the food intake, body weight, and returned the blood pressure to normal levels. This treatment also improved...

Prolactin-releasing peptide (PrRP) is a member of the family of RF-amide peptides. These peptides have typical C-terminal sequence -Arg-Phe-NH2 and similar biological effects. PrRP was discovered as an endogenous ligand of an orphan receptor GPR10 while searching for a factor responsible for a prolactin secretion. This effect was not later confirmed and nowadays, PrRP is mainly considered as an anorexigenic peptide. This is supported by a fact that PrRP and GPR10 deficient mice suffer from hyperphagia and late-onset obesity. Besides GPR10, PrRP is bound to NPFF2 receptor whose endogenous ligand is neuropeptide FF (NPFF). In this study, the PrRP's analogues modified at the N-terminus with fatty acids of different lenghts were tested in vitro on binding and activation MAPK/ERK1/2 signalling pathway. In in vivo experiments on food intake, the central anorexigenic effects of lipidized PrRP-analogues were tested provided their crossing blood brain barrier. Binding studies showed that all analogues bound to rat pituitary RC-4B/C cells with high affinity, analogues containing fatty acid with Ki of one order of magnitude lower than native PrRP. High affinity was also confirmed for binding to cells overexpressing GPR10 receptor and cell membranes with overexpressed NPFF2 receptor. All tested analogues...

Prolactin-releasing peptide (PrRP) and neuropeptide FF (NPFF) belong to the RF-amide family. These peptides have identical C-terminal amino acid sequence (R-F-NH2) and similar biological activities. PrRP was identified as an endogenous ligand of an orphan receptor GPR10 able to stimulate PRL-secretion in vitro and in vivo, but soon it was discoverd that this is not the primary function of this peptide. PrRP is thought to be an anorexigenic peptide as PrRP and GPR10 are found in several parts of the brain responsible for food intake regulation and because both GPR10 and PrRP deficient mice suffer from hyperphagia and late-onset obesity. In this study, relationship between PrRP and NPFF was studied using both in vitro binding and sell signaling and in vivo food intake and analgesia test in mice. In vitro experiments showed that PrRP bound to rat pituitary RC-4B/C cells containing GPR10 receptor with high affinity and NPFF, its stable analog 1DMe and its antagonist RF9 up to 10-5 M concentration did not bind to GPR10. NPFF, 1DMe and PrRP were bound to cell membranes with transfected NPFF2 receptor with high affinity, but RF9 with low affinity in a range of 10-7 M, in contrast to published literature. In vivo experiments with fasted mice confirmed that centrally injected PrRP and NPFF significantly...