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.
Ačkoli jedinců s obezitou neustále přibývá, dostupnost účinné neinvazivní léčby je stále malá. Slibnými prostředky pro léčbu obezity jsou anorexigenní neuropeptidy s působností v mozku. Jejich dopravu do mozku ale komplikuje jejich malá stabilita a omezená schopnost překonat hematoencefalickou bariéru. Nedávno objevené anorexigenní neuropeptidy, jako peptid uvolňující prolaktin, představují nový směr ve vývoji antiobezitních látek. Neuropeptidy jsou uvolňovány a působí přímo v oblastech mozku regulujících příjem potravy, ale obecně neprocházejí hematoencefalickou bariérou po periferním podání. Nám se podařilo navrhnout a syntetizovat stabilní palmitoylované analogy tohoto neuropeptidu, které měly po periferním podání prodloužený akutní anorexigenní účinek v myších a potkanech. Opakované periferní podání palmitoylovaných analogů peptidu uvolňujícího prolaktin vedlo k dlouhodobému antiobezitnímu a antidiabetickému účinku u hlodavců s obezitou navozenou vysokotukovou dietou a s inzulinovou rezistencí. Dokázali jsme, že lipidizace by mohla být účinnou cestou, jak dosáhnout žádoucího centrálního účinku peptidu po jeho periferním podání pro léčbu obezity a vyplývajících komplikací, jako je diabetes 2. typu. Vedle vysokého věku jsou pro Alzheimerovu nemoc rizikovými faktory diabetes 2. typu a obezita. Proto látky snižující koncentraci glukosy v krvi a/nebo s anorexigenními účinky jsou potenciálně neuroprotektivní. Naše skupina sledovala vztah mezi obezitou, diabetem 2. typu a patologickými jevy při Alzheimerově nemoci a zkoumala, zda by originální palmitoylované analogy peptidu uvolňujícího prolaktin mohly působit prospěšně proti neurodegeneraci v několika myších modelech alzheimerovské patologie. Ukázali jsme, že tyto lipidizované analogy jsou potenciálně neuroprotektivní látky, které v myších modelech Alzheimerovy nemoci zlepšují prostorovou paměť, zvyšují neurogenezi, synaptogenezi a potlačují neuroinflamaci a dva hlavní znaky Alzheimerovy nemoci, hyperfosforylaci proteinu tau a vznik plaků amyloidního β‐peptidu.
Obesity is an escalating epidemic, but an effective non-invasive therapy is still scarce. For the obesity treatment, anorexigenic neuropeptides represent promising tools, but their delivery from the periphery to the brain is complicated because peptides have a low stability and limited ability to cross the blood-brain barrier. Recently discovered anorexigenic neuropeptides, such as prolactin-releasing peptide, represent new trends in development of anti-obesity agents. They are released and acting directly in brain areas regulating food intake, but generally do not cross the blood-brain barrier if administered peripherally. We succeeded to design stable palmitoylated analogs of this neuropeptide with a prolonged acute anorexigenic effect after peripheral administration as shown in mice and rats. Repeated peripheral administration of the lipidized prolactin-releasing peptide analogs resulted in long-lasting anti-obesity and antidiabetic effects in rodent models of diet-induced obesity and insulin resistance. We proved that lipidation might be an effective way to transmit the desired effect to the central nervous system after peripheral administration, for a potential treatment of obesity and related complications such as type-2 diabetes. Besides the advanced age, type-2 diabetes and obesity were shown to be risk factors for Alzheimer's disease; therefore, compounds with glucose-lowering and/or anorexigenic properties were proposed to be neuroprotective. In our group, we studied a possible crosstalk between obesity, type-2 diabetes and Alzheimer's-like pathology. We also investigated if our novel palmitoylated analogs of prolactin-releasing peptide could have beneficial effect on neurodegeneration in several mouse models of Alzheimer's-like pathology and their age-matched wild type controls. We demonstrated that these lipidized analogs are potentially neuroprotective substances improving spatial memory, neurogenesis, synaptogenesis and attenuating neuroinflammation and two hallmarks of Alzheimer's disease, i.e., tau hyper-phosphorylation and β-amyloid plaques in different mouse models of Alzheimer's-like neurodegeneration.
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- hormon uvolňující prolaktin * farmakologie terapeutické užití MeSH
- inzulinová rezistence MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- obezita farmakoterapie MeSH
- objevování léků MeSH
- prediabetes farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
BACKGROUND/OBJECTIVE: Anorexigenic palmitoylated prolactin-releasing peptide (palm11-PrRP) is able to act centrally after peripheral administration in rat and mouse models of obesity, type 2 diabetes mellitus and/or neurodegeneration. Functional leptin and intact leptin signaling pathways are necessary for the body weight reducing and glucose tolerance improving effect of palm11-PrRP. We have previously shown that palm11-PrRP31 had glucose-lowering properties but not anti-obesity effect in Koletsky rats with leptin signaling disturbances, so improvements in glucose metabolism appear to be completely independent of leptin signaling. The purpose of this study was to describe relationship between metabolic and neurodegenerative pathologies and explore if palm11-PrRP31 could ameliorate them in obese fa/fa rat model with leptin signaling disruption. SUBJECT/METHODS: The fa/fa rats and their age-matched lean controls at the age 32 weeks were used for this study. The rats were infused for 2 months with saline or palm11-PrRP31 (n = 7-8 per group) at a dose of 5 mg/kg per day using Alzet osmotic pumps. During the dosing period food intake and body weight were monitored. At the end of experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected and arterial blood pressure was measured. Then, markers of leptin and insulin signaling, Tau phosphorylation, neuroinflammation, and synaptogenesis were measured by western blotting and immunohistochemistry. RESULTS: Fa/fa rats developed obesity, mild glucose intolerance, and peripheral insulin resistance but not hypertension while palm11-PrRP31 treatment neither lowered body weight nor attenuated glucose tolerance but ameliorated leptin and insulin signaling and synaptogenesis in hippocampus. CONCLUSION: We demonstrated that palm11-PrRP31 had neuroprotective features without anti-obesity and glucose lowering effects in fa/fa rats. This data suggest that this analog has the potential to exert neuroprotective effect despite of leptin signaling disturbances in this rat model.
- MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- glukosa MeSH
- hormon uvolňující prolaktin farmakologie terapeutické užití MeSH
- inzulin terapeutické užití MeSH
- krysa rodu rattus MeSH
- leptin * MeSH
- myši MeSH
- obezita metabolismus MeSH
- tělesná hmotnost MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Lack of leptin production in ob/ob mice results in obesity and prediabetes that could be partly reversed by leptin supplementation. In the hypothalamus, leptin supports the production of prolactin-releasing peptide (PrRP), an anorexigenic neuropeptide synthesized and active in the brain. In our recent studies, the palmitoylated PrRP analog palm11-PrRP31 showed a central anorexigenic effect after peripheral administration. This study investigates whether PrRP could compensate for the deficient leptin in ob/ob mice. In two separate experiments, palm11-PrRP31 (5 mg/kg) and leptin (5 or 10 μg/kg) were administered subcutaneously twice daily for 2 or 8 weeks to 8- (younger) or 16-(older) week-old ob/ob mice, respectively, either separately or in combination. The body weight decreasing effect of palm11-PrRP31 in both younger and older ob/ob mice was significantly powered by a subthreshold leptin dose, the combined effect could be then considered synergistic. Leptin and palm11-PrRP31 also synergistically lowered liver weight and blood glucose in younger ob/ob mice. Reduced liver weight was linked to decreased mRNA expression of lipogenic enzymes. In the hypothalamus of older ob/ob mice, two main leptin anorexigenic signaling pathways, namely, Janus kinase, signal transducer and activator of transcription-3 activation and AMP-activated protein kinase de-activation, were induced by leptin, palm11-PrRP31, and their combination. Thus, palm11-PrRP31 could partially compensate for leptin deficiency in ob/ob mice. In conclusion, the results demonstrate a synergistic effect of leptin and our lipidized palm11-PrRP31 analog.
- MeSH
- glukózový toleranční test MeSH
- hormon uvolňující prolaktin analogy a deriváty chemie farmakologie terapeutické užití MeSH
- játra účinky léků metabolismus MeSH
- leptin farmakologie terapeutické užití MeSH
- metabolické sítě a dráhy účinky léků MeSH
- metabolismus lipidů účinky léků MeSH
- myši obézní MeSH
- myši MeSH
- obezita farmakoterapie metabolismus MeSH
- přijímání potravy účinky léků MeSH
- synergismus léků MeSH
- tělesná hmotnost účinky léků MeSH
- tělesná teplota MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.
- MeSH
- bludiště - učení účinky léků fyziologie MeSH
- fosforylace účinky léků MeSH
- hipokampus účinky léků metabolismus patologie MeSH
- hormon uvolňující prolaktin analogy a deriváty farmakologie terapeutické užití MeSH
- krátkodobá paměť účinky léků fyziologie MeSH
- modely nemocí na zvířatech MeSH
- myši transgenní MeSH
- neuroprotektivní látky farmakologie MeSH
- poruchy paměti farmakoterapie metabolismus patologie MeSH
- prostorová paměť účinky léků fyziologie MeSH
- proteiny tau metabolismus MeSH
- tauopatie farmakoterapie metabolismus patologie psychologie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND/OBJECTIVES: Prolactin-releasing peptide (PrRP) has a potential to decrease food intake and ameliorate obesity, but is ineffective after peripheral administration. We have previously shown that our novel lipidized analogs PrRP enhances its stability in the circulation and enables its central effect after peripheral application. The purpose of this study was to explore if sub-chronic administration of novel PrRP analog palmitoylated in position 11 (palm11-PrRP31) to Koletsky-spontaneously hypertensive obese rats (SHROB) could lower body weight and glucose intolerance as well as other metabolic parameters. SUBJECTS/METHODS: The SHROB rats (n = 16) were used for this study and age-matched hypertensive lean SHR littermates (n = 16) served as controls. Palm11-PrRP31 was administered intraperitoneally to SHR and SHROB (n = 8) at a dose of 5 mg/kg once-daily for 3 weeks. During the dosing period food intake and body weight were monitored. At the end of the experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected. Thereafter, arterial blood pressure was measured. RESULTS: At the end of the experiment, vehicle-treated SHROB rats showed typical metabolic syndrome parameters, including obesity, glucose intolerance, dyslipidemia, and hypertension. Peripheral treatment with palm11-PrRP31 progressively decreased the body weight of SHR rats but not SHROB rats, though glucose tolerance was markedly improved in both strains. Moreover, in SHROB palm11-PrRP31 ameliorated the HOMA index, insulin/glucagon ratio, and increased insulin receptor substrate 1 and 2 expression in fat and insulin signaling in the hypothalamus, while it had no effect on blood pressure. CONCLUSIONS: We demonstrated that our new lipidized PrRP analog is capable of improving glucose tolerance in obese SHROB rats after peripheral application, suggesting that its effect on glucose metabolism is independent of leptin signaling and body weight lowering. These data suggest that this analog has the potential to be a compound with both anti-obesity and glucose-lowering properties.
- MeSH
- glukagon krev MeSH
- glukózový toleranční test MeSH
- hormon uvolňující prolaktin aplikace a dávkování analogy a deriváty farmakologie terapeutické užití MeSH
- hypertenze krev farmakoterapie MeSH
- inzulin krev metabolismus MeSH
- inzulinová rezistence MeSH
- krevní glukóza metabolismus MeSH
- krevní tlak účinky léků MeSH
- lipidy krev MeSH
- metabolický syndrom * krev farmakoterapie metabolismus MeSH
- mozek účinky léků metabolismus MeSH
- obezita * krev farmakoterapie MeSH
- porucha glukózové tolerance * krev farmakoterapie MeSH
- potkani inbrední SHR MeSH
- proteiny insulinového receptorového substrátu metabolismus MeSH
- tělesná hmotnost účinky léků MeSH
- tuková tkáň účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Obesity is an escalating epidemic, but an effective noninvasive therapy is still scarce. For obesity treatment, anorexigenic neuropeptides are promising tools, but their delivery from the periphery to the brain is complicated because peptides have a low stability and limited ability to cross the blood-brain barrier. In this review, we summarize results of several studies with our newly designed lipidized analogs of prolactin-releasing peptide (PrRP). PrRP is involved in feeding and energy balance regulation as demonstrated by obesity phenotypes of both PrRP- and PrRP-receptor-knockout mice. 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 (NPFF)-2 receptor. Acute peripheral administration of myristoylated and palmitoylated PrRP analogs to mice and rats 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, improved metabolic parameters and attenuated lipogenesis in mice with diet-induced obesity. A strong anorexigenic, body weight-reducing and glucose tolerance-improving effect of palmitoylated-PrRP31 was shown also in diet-induced obese rats after its repeated 2-week-long peripheral administration. Thus, the strong anorexigenic and body weight-reducing effects of palmitoylated PrRP31 and myristoylated PrRP20 make these analogs attractive candidates for antiobesity treatment. Moreover, PrRP receptor might be a new target for obesity therapy.
- MeSH
- hormon uvolňující prolaktin analogy a deriváty terapeutické užití MeSH
- látky proti obezitě farmakologie terapeutické užití MeSH
- lidé MeSH
- obezita farmakoterapie MeSH
- regulace chuti k jídlu * MeSH
- systémy cílené aplikace léků * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
