Prolactin-releasing peptide (PrRP) has been proposed to mediate the central satiating effects of cholecystokinin (CCK) through the vagal CCK1 receptor. PrRP acts as an endogenous ligand of G protein-coupled receptor 10 (GPR10), which is expressed at the highest levels in brain areas related to food intake regulation, e.g., the paraventricular hypothalamic nucleus (PVN) and nucleus of the solitary tract (NTS). The NTS and PVN are also significantly activated after peripheral CCK administration. The aim of this study was to determine whether the endogenous PrRP neuronal system in the brain is involved in the central anorexigenic effect of the peripherally administered CCK agonist JMV236 or the CCK1 antagonist devazepide and whether the CCK system is involved in the central anorexigenic effect of the peripherally applied lipidized PrRP analog palm-PrRP31 in fasted lean mice. The effect of devazepide and JMV236 on the anorexigenic effects of palm-PrRP31 as well as devazepide combined with JMV236 and palm-PrRP31 on food intake and Fos cell activation in the PVN and caudal NTS was examined. Our results suggest that the anorexigenic effect of JMV236 is accompanied by activation of PrRP neurons of the NTS in a CCK1 receptor-dependent manner. Moreover, while the anorexigenic effect of palm-PrRP31 was not affected by JMV236, it was partially attenuated by devazepide in fasted mice. The present findings indicate that the exogenously influenced CCK system may be involved in the central anorexigenic effect of peripherally applied palm-PrRP31, which possibly indicates some interaction between the CCK and PrRP neuronal systems.

• MeSH
• Appetite Depressants administration & dosage   MeSH
• Hormone Antagonists administration & dosage   MeSH
• Chemokines, CC drug effects   metabolism   MeSH
• Cholecystokinin metabolism   MeSH
• Devazepide administration & dosage   MeSH
• Prolactin-Releasing Hormone administration & dosage   analogs & derivatives   MeSH
• Injections, Intraperitoneal MeSH
• Injections, Subcutaneous MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Paraventricular Hypothalamic Nucleus drug effects   metabolism   MeSH
• Solitary Nucleus drug effects   metabolism   MeSH
• Fasting MeSH
• Peptide Fragments administration & dosage   MeSH
• Eating drug effects   MeSH
• Proto-Oncogene Proteins c-fos metabolism   MeSH
• Signal Transduction MeSH
• Sincalide administration & dosage   analogs & derivatives   MeSH
• Feeding Behavior drug effects   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Appetite Depressants MeSH
• Hormone Antagonists MeSH
• Ccl28 protein, mouse MeSH Browser
• Chemokines, CC MeSH
• Cholecystokinin MeSH
• Devazepide MeSH
• Fos protein, mouse MeSH Browser
• Prolactin-Releasing Hormone MeSH
• JMV 236 MeSH Browser
• palm11-PrRP31 MeSH Browser
• Peptide Fragments MeSH
• Proto-Oncogene Proteins c-fos MeSH
• Sincalide MeSH

OBJECTIVES: Obesity is a frequent metabolic disorder but an effective therapy is still scarce. Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity but are ineffective after peripheral application. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both PrRP- and PrRP-receptor-knockout mice. RESULTS: Lipidized PrRP analogs showed binding affinity and signaling in PrRP receptor-expressing cells similar to natural PrRP. Moreover, these analogs showed high binding affinity also to anorexigenic neuropeptide FF-2 receptor. Peripheral administration of myristoylated and palmitoylated PrRP analogs to fasted mice induced strong and long-lasting anorexigenic effects and neuronal activation in the brain areas involved in food intake regulation. Two-week-long subcutaneous administration of palmitoylated PrRP31 and myristoylated PrRP20 lowered food intake, body weight and improved metabolic parameters, and attenuated lipogenesis in mice with diet-induced obesity. CONCLUSIONS: Our data suggest that the lipidization of PrRP enhances stability and mediates its effect in central nervous system. Strong anorexigenic and body-weight-reducing effects make lipidized PrRP an attractive candidate for anti-obesity treatment.

• MeSH
• Energy Metabolism MeSH
• Prolactin-Releasing Hormone analogs & derivatives   pharmacology   MeSH
• Anti-Obesity Agents pharmacology   MeSH
• Lipids chemistry   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Obesity prevention & control   MeSH
• Half-Life MeSH
• Eating MeSH
• Appetite Regulation MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Prolactin-Releasing Hormone MeSH
• Anti-Obesity Agents MeSH
• Lipids MeSH

In our study on non coded amino acids and their utilization in peptide chemistry we synthesized methylene-thio (CH2-S) and methyleneoxy (CH2-O) group containing amino acids and pseudodipeptides which could be used as building blocks for the construction of peptide hormone analogues. The (CH2-S) isoster of peptide bond exhibits increased flexibility, lipophility and resistance to proteolytic enzymes. This group exhibits similar properties as the isosteric disulfide bond in the side chain of cystine residue. The (CH2-O) isoster is moreover similar in its geometry to extended conformation of peptide bond. As a consequence, the changed profile of biological activities could be expected for peptide hormone analogues containing such isosteric moiety. The (CH2-S) isosters of the peptide bond were prepared by alkylation of thiolates of 2-mercaptocarboxylic acids, the disulfide bond by alkylation of cysteine or homocysteine. The (CH2-O) isosters were prepared by (AcO)4Rh2 catalyzed addition of carbenes of alkyl diazocarboxylates to N-protected aminoalcohols. Pseudodipeptides H-Leu-ψ(CH2-S)-Gly-NH2 and H-Leu-ψ(CH2-O)-Gly-NH2 were introduced into the C-terminal part of the oxytocin molecule using solution methods of peptide chemistry. Both inserted isosteric bonds were resistant against proteolytic degradation, the first one was found to decrease an enzymic cleavage of the distant Tyr(2)-Ile(3) bond in the corresponding analogue, too. The (CH2-S) isosters of the disulfide bond containing an orthogonal protection of theirα-amino (Fmoc) andα-(OAll, OH) orω-(OBu(+), OH) carboxylic groups were applied in the solid phase synthesis of the aminoterminal 1-deamino-15-pentadecapeptide of endothelin-I which represents a strong vasoactive agent. The solid phase synthesis was carried out by the step-wise protocol on the Rink or Merrifield type resin using orthogonally protected carba cystine building blocks.

• Publication type
• Journal Article MeSH