Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide expressed in the brain where it regulates food intake and energy expenditure. The C-terminal Arg-Phe-NH2 of PrRP is crucial for its biological activity. In our previous study, we showed that PrRP analogs myristoylated or palmitoylated at the N- terminus seem to cross the blood-brain barrier and lower food intake following peripheral administration. In this study, myristoylated and palmitoylated PrRP31 analogs with a modified C-terminal Phe were designed and tested. Lipidized analogs containing Phe(31) replaced by aromatic non-coded amino acids or tyrosine revealed high binding affinity to rat pituitary RC-4B/C cells with endogenous PrRP and neuropeptide FF 2 receptors and to CHO-K1 cells overexpressing either PrRP or neuropeptide FF 2 receptors. The analogs also showed strong agonistic properties at the GPR10 receptor using the beta-lactamase reporter gene assay. Moreover, lipidized PrRP analogs, especially those that were palmitoylated, demonstrated strong and long-lasting anorexigenic effects in fasted mice after subcutaneous administration. The most efficient PrRP31 analogs with PheCl2(31), either palmitoylated or myristoylated at the N-terminus, are promising candidates for the study of food disorders, possibly for anti-obesity treatment. Despite the therapeutic potential in targeting central GPR10, the endogenous ligand PrRP cannot cross the blood-brain barrier. Understanding biological activity and transport of novel structural analogs of PrRP with a potential central anorexigenic effect is of key therapeutic significance.

• MeSH
• buněčné linie MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• hematoencefalická bariéra metabolismus   MeSH
• hormon uvolňující prolaktin analogy a deriváty   metabolismus   farmakologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• lipidy MeSH
• mozek metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neuropeptidy metabolismus   farmakologie   MeSH
• obezita farmakoterapie   metabolismus   MeSH
• přijímání potravy účinky léků   MeSH
• receptory neuropeptidů metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem 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
• energetický metabolismus MeSH
• hormon uvolňující prolaktin analogy a deriváty   farmakologie   MeSH
• látky proti obezitě farmakologie   MeSH
• lipidy chemie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita prevence a kontrola   MeSH
• poločas MeSH
• přijímání potravy MeSH
• regulace chuti k jídlu MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakty MeSH

It was demonstrated that estrogen deficiency and consuming high fat (HF) diet enhanced orexigenic activity of ghrelin. Therefore, we hypothesized that antagonizing of ghrelin action would attenuate food intake and body weight in mice obese both from ovariectomy (OVX) and feeding a HF diet. Ghrelin receptor antagonist [D-Lys(3)]GHRP-6 after seven days of subcutaneous treatment markedly decreased food intake in OVX mice fed both HF and standard diets; furthermore, it reduced body weight and blood glucose, insulin and leptin, and increased β-hydroxybutyrate level and uncoupling-protein-1 mRNA in brown adipose tissue. Pair-feeding revealed that effect of [D-Lys(3)]GHRP-6 was primary anorexigenic. Estrogen supplementation reduced anorexigenic effects of [D-Lys(3)]GHRP-6. OVX [D-Lys(3)]GHRP-6 treatment in mice on HF diet resulted in markedly increased circulating level and liver expression of a major metabolic regulator, fibroblast growth factor 21. Our data suggest that ghrelin antagonists could be especially beneficial in individuals with common obesity combined with estrogen deficiency.

• MeSH
• adipozita účinky léků   MeSH
• chování zvířat účinky léků   MeSH
• dieta s vysokým obsahem tuků MeSH
• estrogeny aplikace a dávkování   nedostatek   MeSH
• ghrelin metabolismus   MeSH
• hnědá tuková tkáň metabolismus   MeSH
• iontové kanály genetika   metabolismus   MeSH
• lidé MeSH
• mitochondriální proteiny genetika   metabolismus   MeSH
• modely u zvířat MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita patofyziologie   MeSH
• oligopeptidy farmakologie   MeSH
• ovarektomie MeSH
• pohybová aktivita účinky léků   MeSH
• postmenopauza metabolismus   MeSH
• PPAR alfa genetika   metabolismus   MeSH
• přenašeč glukosy typ 1 genetika   metabolismus   MeSH
• přijímání potravy účinky léků   MeSH
• receptory ghrelinu antagonisté a inhibitory   genetika   metabolismus   MeSH
• tělesná hmotnost účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH