Koletsky rats, the genetically obese strain of spontaneously hypertensive rats (SHROB), are the well-accepted animal model of human metabolic syndrome. They are characterized by early onset obesity, spontaneous hypertension, hyperinsulinemia, hyperlipidemia, proteinuria and shortened life-span. One of the factors in the pathogenesis of metabolic syndrome is oxidative stress. The aim of the present study was to compare two parameters related to oxidative stress: the levels of the main intracellular antioxidant, reduced glutathione as well as the indirect indicator of lipid peroxidation damage, thiobarbituric acid-reactive substances (TBARS) in heart, renal cortex and medulla and liver in male lean spontaneously hypertensive rats (SHR) and obese Koletsky rats. We did not find any significant differences in these markers in heart and kidneys. However, we found significantly lower glutathione level in Koletsky rat liver compared with SHR (5.03+/-0.23 vs. 5.83+/-0.14 µmol/g tissue, respectively). On the contrary, we observed significantly higher TBARS levels in Koletsky rat liver compared with SHR (28.56+/-2.15 vs. 21.83+/-1.60 nmol/mg protein, respectively). We conclude that the liver is the most sensitive tissue to oxidative damage with the significantly decreased concentration of glutathione and the significantly increased concentration of TBARS in obese Koletsky rats in comparison with lean control SHR.

• MeSH
• glutathion * metabolismus   MeSH
• hypertenze metabolismus   MeSH
• játra * metabolismus   MeSH
• krysa rodu Rattus MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• ledviny metabolismus   MeSH
• myokard metabolismus   MeSH
• obezita * metabolismus   MeSH
• oxidační stres * fyziologie   MeSH
• peroxidace lipidů * MeSH
• potkani inbrední SHR * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glutathion * MeSH
• látky reagující s kyselinou thiobarbiturovou MeSH

A previous study on neuropeptide FF receptor 2 (NPFFR2)-deficient mice has demonstrated that NPFFR2 is involved in the control of energy balance and thermogenesis. Here, we report on the metabolic impact of NPFFR2 deficiency in male and female mice that were fed either a standard diet (STD) or a high-fat diet (HFD) and each experimental group consisted of ten individuals. Both male and female NPFFR2 knockout (KO) mice exhibited severe glucose intolerance that was exacerbated by a HFD diet. In addition, reduced insulin pathway signaling proteins in NPFFR2 KO mice fed a HFD resulted in the development of hypothalamic insulin resistance. HFD feeding did not cause liver steatosis in NPFFR2 KO mice of either sex, but NPFFR2 KO male mice fed a HFD had lower body weights, white adipose tissues, and liver and lower plasma leptin levels compared with their wild-type (WT) controls. Lower liver weight in NPFFR2 KO male mice compensated for HFD-induced metabolic stress by increased liver PPARα and plasma FGF21 hepatokine, which supported fatty acid β-oxidation in the liver and white adipose tissue. Conversely, NPFFR2 deletion in female mice attenuated the expression of Adra3β and Pparγ, which inhibited lipolysis in adipose tissue.

• Klíčová slova
• glucose intolerance, high-fat diet, insulin resistance, knockout mice, neuropeptide FF,
• MeSH
• bílá tuková tkáň metabolismus   MeSH
• dieta s vysokým obsahem tuků MeSH
• glukosa metabolismus   MeSH
• inzulinová rezistence * MeSH
• játra metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• obezita metabolismus   MeSH
• porucha glukózové tolerance * metabolismus   MeSH
• tuková tkáň metabolismus   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
• glukosa MeSH
• neuropeptide FF receptor MeSH Prohlížeč

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

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
• Názvy látek
• glukosa MeSH
• hormon uvolňující prolaktin MeSH
• inzulin MeSH
• leptin * 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), a natural ligand for the GPR10 receptor, is a neuropeptide with anorexigenic and antidiabetic properties. Due to its role in the regulation of food intake, PrRP is a potential drug for obesity treatment and associated type 2 diabetes mellitus (T2DM). Recently, the neuroprotective effects of lipidized PrRP analogs have been proven. In this study, we focused on the molecular mechanisms of action of natural PrRP31 and its lipidized analog palm11-PrRP31 in the human neuroblastoma cell line SH-SY5Y to describe their cellular signaling and possible anti-apoptotic properties. PrRP31 significantly upregulated the phosphoinositide-3 kinase-protein kinase B/Akt (PI3K-PKB/Akt) and extracellular signal-regulated kinase/cAMP response element-binding protein (ERK-CREB) signaling pathways that promote metabolic cell survival and growth. In addition, we proved via protein kinase inhibitors that activation of signaling pathways is mediated specifically by PrRP31 and its palmitoylated analog. Furthermore, the potential neuroprotective properties were studied through activation of anti-apoptotic pathways of PrRP31 and palm11-PrRP31 using the SH-SY5Y cell line and rat primary neuronal culture stressed with toxic methylglyoxal (MG). The results indicate increased viability of the cells treated with PrRP and palm11-PrRP31 and a reduced degree of apoptosis induced by MG, suggesting their potential use in the treatment of neurological disorders.

• Klíčová slova
• SH-SY5Y, cellular signaling, inhibitors, methylglyoxal, neuroprotection, primary neuronal culture, prolactin-releasing peptide,
• MeSH
• apoptóza * MeSH
• hormon uvolňující prolaktin chemie   farmakologie   MeSH
• lidé MeSH
• nádorové buňky kultivované MeSH
• neuroblastom farmakoterapie   metabolismus   patologie   MeSH
• neuropeptidy chemie   farmakologie   MeSH
• neuroprotektivní látky chemie   farmakologie   MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hormon uvolňující prolaktin MeSH
• neuropeptidy MeSH
• neuroprotektivní látky MeSH
• proteiny regulující apoptózu 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