Anti-obesity medications (AOMs) have become one of the most prescribed drugs in human medicine. While AOMs are known to impact adult neurogenesis in the hypothalamus, their effects on the functional maturation of hypothalamic neurons remain unexplored. Given that AOMs target neurons in the Medial Basal Hypothalamus (MBH), which play a crucial role in regulating energy homeostasis, we hypothesized that AOMs might influence the functional maturation of these neurons, potentially rewiring the MBH. To investigate this, we exposed hypothalamic neurons derived from human induced pluripotent stem cells (hiPSCs) to Semaglutide and lipidized prolactin-releasing peptide (LiPR), two anti-obesity compounds. Contrary to our expectations, treatment with Semaglutide or LiPR during neuronal maturation did not affect the proportion of anorexigenic, Pro-opiomelanocortin-expressing (POMC+) neurons. Additionally, LiPR did not alter the morphology of POMC+ neurons or the expression of selected genes critical for the metabolism or development of anorexigenic neurons. Furthermore, LiPR did not impact the proportion of adult-generated POMC+ neurons in the mouse MBH. Taken together, these results suggest that AOMs do not influence the functional maturation of anorexigenic hypothalamic neurons.

• Publikační typ
• časopisecké články MeSH

Coordination compounds of lanthanides are indispensable in biomedical applications as MRI contrast agents and radiotherapeutics. However, since the introduction of the chelator DOTA four decades ago, there has been only limited progress on improving their thermodynamic stability and kinetic inertness, which are essential for safe in vivo use. Here, we present ClickZip, an innovative synthetic strategy employing a coordination-templated formation of a 1,5-triazole bridge that improves kinetic inertness up to a million-fold relative to DOTA, expanding utility of lanthanide chelates beyond traditional uses. Acting as unique mass tags, the ClickZip chelates can be released from (biological) samples by acidic hydrolysis, chromatographically distinguished from interfering lanthanide species, and sensitively detected by mass spectrometry. Lanthanides enclosed in ClickZip chelates are chemically almost indistinguishable, providing a more versatile alternative to chemically identical isotopic labels for multiplexed analysis. The bioanalytical potential is demonstrated on tagged cell-penetrating peptides in vitro, and anti-obesity prolactin-releasing peptides in vivo.

• MeSH
• chelátory * chemie   MeSH
• hmotnostní spektrometrie metody   MeSH
• kinetika MeSH
• kontrastní látky chemie   MeSH
• lanthanoidy * chemie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• myši MeSH
• triazoly chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory * MeSH
• kontrastní látky MeSH
• lanthanoidy * MeSH
• triazoly MeSH

Since 1975, the incidence of obesity has increased to epidemic proportions, and the number of patients with obesity has quadrupled. Obesity is a major risk factor for developing other serious diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Recent epidemiologic studies have defined obesity as a risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and other types of dementia. Despite all these serious comorbidities associated with obesity, there is still a lack of effective antiobesity treatment. Promising candidates for the treatment of obesity are anorexigenic neuropeptides, which are peptides produced by neurons in brain areas implicated in food intake regulation, such as the hypothalamus or the brainstem. These peptides efficiently reduce food intake and body weight. Moreover, because of the proven interconnection between obesity and the risk of developing AD, the potential neuroprotective effects of these two agents in animal models of neurodegeneration have been examined. The objective of this review was to explore anorexigenic neuropeptides produced and acting within the brain, emphasizing their potential not only for the treatment of obesity but also for the treatment of neurodegenerative disorders.

• Klíčová slova
• Alzheimer´s-like pathology, anorexigenic neuropeptides, antiobesity treatment, neuroprotection,
• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   patologie   prevence a kontrola   MeSH
• hypothalamus účinky léků   metabolismus   patologie   MeSH
• látky proti obezitě * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mozek účinky léků   metabolismus   patologie   MeSH
• neurodegenerativní nemoci farmakoterapie   metabolismus   prevence a kontrola   MeSH
• neuropeptidy * metabolismus   farmakologie   terapeutické užití   MeSH
• neuroprotektivní látky * farmakologie   terapeutické užití   MeSH
• obezita * farmakoterapie   metabolismus   MeSH
• přijímání potravy účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• látky proti obezitě * MeSH
• neuropeptidy * MeSH
• neuroprotektivní látky * 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) is an anorexigenic neuropeptide that has potential for the treatment of obesity and its complications. Recently, we designed a palmitoylated PrRP31 analog (palm11-PrRP31) that is more stable than the natural peptide and able to act centrally after peripheral administration. This analog acted as an anti-obesity and glucose-lowering agent, attenuating lipogenesis in rats and mice with high-fat (HF) diet-induced obesity. In Wistar Kyoto (WKY) rats fed a HF diet for 52 weeks, we explored glucose intolerance, but also prediabetes, liver steatosis and insulin resistance-related changes, as well as neuroinflammation in the brain. A potential beneficial effect of 6 weeks of treatment with palm11-PrRP31 and liraglutide as comparator was investigated. Liver lipid profiles, as well as urinary and plasma metabolomic profiles, were measured by lipidomics and metabolomics, respectively. Old obese WKY rats showed robust glucose intolerance that was attenuated by palm11-PrRP31, but not by liraglutide treatment. On the contrary, liraglutide had a beneficial effect on insulin resistance parameters. Despite obesity and prediabetes, WKY rats did not develop steatosis owing to HF diet feeding, even though liver lipogenesis was enhanced. Plasma triglycerides and cholesterol were not increased by HFD feeding, which points to unincreased lipid transport from the liver. The liver lipid profile was significantly altered by a HF diet that remained unaffected by palm11-PrRP31 or liraglutide treatment. The HF-diet-fed WKY rats revealed astrogliosis in the brain cortex and hippocampus, which was attenuated by treatment. In conclusion, this study suggested multiple beneficial anti-obesity-related effects of palm11-PrRP31 and liraglutide in both the periphery and brain.

• Klíčová slova
• Wistar Kyoto rats, astrocytosis, diet-induced obesity, glucose intolerance, lipid metabolism, lipidomics, liraglutide, metabolomics, prolactin-releasing peptide,
• MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• hormon uvolňující prolaktin farmakologie   MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• inzulinová rezistence * MeSH
• krysa rodu Rattus MeSH
• lipidy MeSH
• liraglutid farmakologie   terapeutické užití   MeSH
• myši MeSH
• obezita farmakoterapie   MeSH
• porucha glukózové tolerance * farmakoterapie   MeSH
• potkani inbrední WKY MeSH
• prediabetes * farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hormon uvolňující prolaktin MeSH
• hypoglykemika MeSH
• lipidy MeSH
• liraglutid MeSH

Obesity and type 2 diabetes mellitus (T2DM) are preconditions for the development of metabolic syndrome, which is reaching pandemic levels worldwide, but there are still only a few anti-obesity drugs available. One of the promising tools for the treatment of obesity and related metabolic complications is anorexigenic peptides, such as prolactin-releasing peptide (PrRP). PrRP is a centrally acting neuropeptide involved in food intake and body weight (BW) regulation. In its natural form, it has limitations for peripheral administration; thus, we designed analogs of PrRP lipidized at the N-terminal region that showed high binding affinities, increased stability and central anorexigenic effects after peripheral administration. In this review, we summarize the preclinical results of our chronic studies on the pharmacological role of the two most potent palmitoylated PrRP31 analogs in various mouse and rat models of obesity, glucose intolerance, and insulin resistance. We used mice and rats with diet-induced obesity fed a high-fat diet, which is considered to simulate the most common form of human obesity, or rodent models with leptin deficiency or disrupted leptin signaling in which long-term food intake regulation by leptin is distorted. The rodent models described in this review are models of metabolic syndrome with different severities, such as obesity or morbid obesity, prediabetes or diabetes and hypertension. We found that the effects of palmitoylated PrRP31 on food intake and BW but not on glucose intolerance require intact leptin signaling. Thus, palmitoylated PrRP31 analogs have potential as therapeutics for obesity and related metabolic complications.

• Klíčová slova
• leptin resistance, obesity, prolactin-releasing peptide, rodent models, type 2 diabetes,
• Publikační typ
• časopisecké články MeSH
• přehledy 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

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
• Názvy látek
• glukagon MeSH
• hormon uvolňující prolaktin MeSH
• inzulin MeSH
• krevní glukóza MeSH
• lipidy MeSH
• proteiny insulinového receptorového substrátu MeSH