GPR10 and neuropeptide FF receptor 2 (NPFFR2) play important role in the regulation of food intake and energy homeostasis. Understanding the interaction between these receptors and their specific ligands, such as prolactin-releasing peptide, is essential for developing stable peptide analogs with potential for treating obesity. By breeding and characterizing double knockout (dKO) mice fed standard or high-fat diet (HFD), we provide insights into the metabolic regulation associated with the GPR10 and NPFFR2 deficiency. Both WT and dKO mice were subjected to behavioral tests and an oral glucose tolerance test. Moreover, dual-energy X-ray absorptiometry (DEXA) followed by indirect calorimetry were performed to characterize dKO mice. dKO mice of both sexes, when exposed to an HFD, showed reduced glucose tolerance, hyperinsulinemia, and insulin resistance compared with controls. Moreover, they displayed increased liver weight with worsened hepatic steatosis. Mice displayed significantly increased body weight, which was more pronounced in dKO males and caused by higher caloric intake on a standard diet, while dKO females displayed obesity characterized by increased white adipose tissue and enhanced hepatic lipid accumulation on an HFD. Moreover, dKO females exhibited anxiety-like behavior in the open field test. dKO mice on a standard diet had a lower respiratory quotient, with no significant changes in energy expenditure. These results provide insights into alterations associated with disrupted GPR10 and NPFFR2 signaling, contributing to the development of potential anti-obesity treatment.

• Klíčová slova
• GPR10/NPFFR2-deficient mice, double KO mice, impaired glucose utilization, insulin resistance, obesity,
• MeSH
• bílá tuková tkáň metabolismus   MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• energetický metabolismus genetika   MeSH
• inzulinová rezistence MeSH
• myši inbrední C57BL MeSH
• myši knockoutované * MeSH
• myši MeSH
• obezita * metabolismus   genetika   MeSH
• prediabetes * metabolismus   genetika   MeSH
• receptory neuropeptidů * genetika   metabolismus   nedostatek   MeSH
• receptory spřažené s G-proteiny * genetika   metabolismus   nedostatek   MeSH
• sexuální faktory MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• neuropeptide FF receptor MeSH Prohlížeč
• receptory neuropeptidů * MeSH
• receptory spřažené s G-proteiny * MeSH

Hypothalamic Adult Neurogenesis (hAN) has been implicated in regulating energy homeostasis. Adult-generated neurons and adult Neural Stem Cells (aNSCs) in the hypothalamus control food intake and body weight. Conversely, diet-induced obesity (DIO) by high fat diets (HFD) exerts adverse influence on hAN. However, the effects of anti-obesity compounds on hAN are not known. To address this, we administered a lipidized analogue of an anti-obesity neuropeptide, Prolactin Releasing Peptide (PrRP), so-called LiPR, to mice. In the HFD context, LiPR rescued the survival of adult-born hypothalamic neurons and increased the number of aNSCs by reducing their activation. LiPR also rescued the reduction of immature hippocampal neurons and modulated calcium dynamics in iPSC-derived human neurons. In addition, some of these neurogenic effects were exerted by another anti-obesity compound, Liraglutide. These results show for the first time that anti-obesity neuropeptides influence adult neurogenesis and suggest that the neurogenic process can serve as a target of anti-obesity pharmacotherapy.

• Klíčová slova
• Adult neurogenesis, Anti-obesity peptides, Hypothalamus, Neural stem cells, Prolactin Releasing Peptide,
• MeSH
• hormon uvolňující prolaktin farmakologie   terapeutické užití   MeSH
• hypothalamus MeSH
• lidé MeSH
• myši MeSH
• neurogeneze MeSH
• neuropeptidy * MeSH
• obezita * farmakoterapie   MeSH
• tělesná hmotnost MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hormon uvolňující prolaktin MeSH
• neuropeptidy * MeSH

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
• anorektika aplikace a dávkování   MeSH
• antagonisté hormonů aplikace a dávkování   MeSH
• chemokiny CC účinky léků   metabolismus   MeSH
• cholecystokinin metabolismus   MeSH
• devazepid aplikace a dávkování   MeSH
• hormon uvolňující prolaktin aplikace a dávkování   analogy a deriváty   MeSH
• injekce intraperitoneální MeSH
• injekce subkutánní MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nucleus paraventricularis hypothalami účinky léků   metabolismus   MeSH
• nucleus solitarius účinky léků   metabolismus   MeSH
• omezení příjmu potravy MeSH
• peptidové fragmenty aplikace a dávkování   MeSH
• přijímání potravy účinky léků   MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• signální transdukce MeSH
• sinkalid aplikace a dávkování   analogy a deriváty   MeSH
• stravovací zvyklosti účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anorektika MeSH
• antagonisté hormonů MeSH
• Ccl28 protein, mouse MeSH Prohlížeč
• chemokiny CC MeSH
• cholecystokinin MeSH
• devazepid MeSH
• Fos protein, mouse MeSH Prohlížeč
• hormon uvolňující prolaktin MeSH
• JMV 236 MeSH Prohlížeč
• palm11-PrRP31 MeSH Prohlížeč
• peptidové fragmenty MeSH
• protoonkogenní proteiny c-fos MeSH
• sinkalid MeSH

The anorexigenic neuropeptide prolactin-releasing peptide (PrRP) is involved in the regulation of food intake and energy expenditure. Lipidization of PrRP stabilizes the peptide, facilitates central effect after peripheral administration and increases its affinity for its receptor, GPR10, and for the neuropeptide FF (NPFF) receptor NPFF-R2. The two most potent palmitoylated analogs with anorectic effects in mice, palm11-PrRP31 and palm-PrRP31, were studied in vitro to determine their agonist/antagonist properties and mechanism of action on GPR10, NPFF-R2 and other potential off-target receptors related to energy homeostasis. Palmitoylation of both PrRP31 analogs increased the binding properties of PrRP31 to anorexigenic receptors GPR10 and NPFF-R2 and resulted in a high affinity for another NPFF receptor, NPFF-R1. Moreover, in CHO-K1 cells expressing GPR10, NPFF-R2 or NPFF-R1, palm11-PrRP and palm-PrRP significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (Akt) and cAMP-responsive element-binding protein (CREB). Palm11-PrRP31, unlike palm-PrRP31, did not activate either c-Jun N-terminal kinase (JNK), p38, c-Jun, c-Fos or CREB pathways in cells expressing NPFF-1R. Palm-PrRP31 also has higher binding affinities for off-target receptors, namely, the ghrelin, opioid (KOR, MOR, DOR and OPR-L1) and neuropeptide Y (Y1, Y2 and Y5) receptors. Palm11-PrRP31 exhibited fewer off-target activities; therefore, it has a higher potential to be used as an anti-obesity drug with anorectic effects.

• Klíčová slova
• GPR10, NPFF-R1, NPFF-R2, binding properties, neuropeptide FF, prolactin-releasing peptide, signaling pathways,
• MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• hormon uvolňující prolaktin chemie   genetika   metabolismus   MeSH
• křečci praví MeSH
• lidé MeSH
• lipoylace * MeSH
• receptory neuropeptidů genetika   metabolismus   MeSH
• receptory spřažené s G-proteiny genetika   metabolismus   MeSH
• techniky in vitro MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hormon uvolňující prolaktin MeSH
• neuropeptide FF receptor MeSH Prohlížeč
• PRLH protein, human MeSH Prohlížeč
• PRLHR protein, human MeSH Prohlížeč
• receptory neuropeptidů MeSH
• receptory spřažené s G-proteiny MeSH
• vápník MeSH

Prolactin-releasing peptide (PrRP) belongs to the large RF-amide neuropeptide family with a conserved Arg-Phe-amide motif at the C-terminus. PrRP plays a main role in the regulation of food intake and energy expenditure. This review focuses not only on the physiological functions of PrRP, but also on its pharmacological properties and the actions of its G-protein coupled receptor, GPR10. Special attention is paid to structure-activity relationship studies on PrRP and its analogs as well as to their effect on different physiological functions, mainly their anorexigenic and neuroprotective features and the regulation of the cardiovascular system, pain, and stress. Additionally, the therapeutic potential of this peptide and its analogs is explored.

• Klíčová slova
• GPR10, RF-amide peptides, energy expenditure, food intake regulation, neuroprotection, prolactin-releasing peptide, signaling,
• MeSH
• energetický metabolismus účinky léků   MeSH
• hormon uvolňující prolaktin chemie   metabolismus   farmakologie   MeSH
• lidé MeSH
• neurodegenerativní nemoci farmakoterapie   patologie   MeSH
• neuroprotektivní látky chemie   farmakologie   terapeutické užití   MeSH
• přijímání potravy účinky léků   MeSH
• receptory spřažené s G-proteiny chemie   genetika   metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• hormon uvolňující prolaktin MeSH
• neuroprotektivní látky MeSH
• PRLHR protein, human MeSH Prohlížeč
• receptory spřažené s G-proteiny 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
• Názvy látek
• hormon uvolňující prolaktin MeSH
• látky proti obezitě MeSH
• lipidy MeSH