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1.
Nutr Diabetes ; 8(1): 5, 2018 01 16.
Article in English | MEDLINE | ID: mdl-29339795

ABSTRACT

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.


Subject(s)
Blood Glucose/metabolism , Body Weight/drug effects , Glucose Intolerance , Hypertension/blood , Metabolic Syndrome , Obesity , Prolactin-Releasing Hormone/pharmacology , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Blood Pressure/drug effects , Brain/drug effects , Brain/metabolism , Glucagon/blood , Glucose Intolerance/blood , Glucose Intolerance/drug therapy , Glucose Tolerance Test , Hypertension/drug therapy , Insulin/blood , Insulin/metabolism , Insulin Receptor Substrate Proteins/metabolism , Insulin Resistance , Lipids/blood , Male , Metabolic Syndrome/blood , Metabolic Syndrome/drug therapy , Metabolic Syndrome/metabolism , Obesity/blood , Obesity/drug therapy , Prolactin-Releasing Hormone/administration & dosage , Prolactin-Releasing Hormone/analogs & derivatives , Prolactin-Releasing Hormone/therapeutic use , Rats, Inbred SHR
2.
PLoS One ; 12(8): e0183449, 2017.
Article in English | MEDLINE | ID: mdl-28820912

ABSTRACT

Analogs of anorexigenic neuropeptides, such as prolactin-releasing peptide (PrRP), have a potential as new anti-obesity drugs. In our previous study, palmitic acid attached to the N-terminus of PrRP enabled its central anorexigenic effects after peripheral administration. In this study, two linkers, γ-glutamic acid at Lys11 and a short, modified polyethylene glycol at the N-terminal Ser and/or Lys11, were applied for the palmitoylation of PrRP31 to improve its bioavailability. These analogs had a high affinity and activation ability to the PrRP receptor GPR10 and the neuropeptide FF2 receptor, as well as short-term anorexigenic effect similar to PrRP palmitoylated at the N-terminus. Two-week treatment with analogs that were palmitoylated through linkers to Lys11 (analogs 1 and 2), but not with analog modified both at the N-terminus and Lys11 (analog 3) decreased body and liver weights, insulin, leptin, triglyceride, cholesterol and free fatty acid plasma levels in a mouse model of diet-induced obesity. Moreover, the expression of uncoupling protein-1 was increased in brown fat suggesting an increase in energy expenditure. In addition, treatment with analogs 1 and 2 but not analog 3 significantly decreased urinary concentrations of 1-methylnicotinamide and its oxidation products N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide, as shown by NMR-based metabolomics. This observation confirmed the previously reported increase in nicotinamide derivatives in obesity and type 2 diabetes mellitus and the effectiveness of analogs 1 and 2 in the treatment of these disorders.


Subject(s)
Diet , Obesity/metabolism , Peptides/pharmacology , Prolactin-Releasing Hormone/metabolism , Amino Acid Sequence , Animals , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Male , Metabolomics , Mice , Mice, Inbred C57BL , Nuclear Magnetic Resonance, Biomolecular , Obesity/etiology , Peptides/chemistry , Prolactin-Releasing Hormone/chemistry , beta-Lactamases/metabolism
3.
J Endocrinol ; 230(2): R51-8, 2016 08.
Article in English | MEDLINE | ID: mdl-27418033

ABSTRACT

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.


Subject(s)
Anti-Obesity Agents/therapeutic use , Appetite Regulation , Drug Delivery Systems , Obesity/drug therapy , Prolactin-Releasing Hormone/therapeutic use , Animals , Anti-Obesity Agents/pharmacology , Humans , Prolactin-Releasing Hormone/analogs & derivatives
4.
J Endocrinol ; 229(2): 85-96, 2016 05.
Article in English | MEDLINE | ID: mdl-26906745

ABSTRACT

Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity, but are ineffective after peripheral application, owing to a limited ability to cross the blood-brain barrier. 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-knockout and Prrp receptor-knockout mice. The aim of this study was to characterize the subchronic effect of a palmitoylated PrRP analog in two rat models of obesity and diabetes: diet-induced obese Sprague-Dawley rats and leptin receptor-deficient Zucker diabetic (ZDF) rats. In the rats with diet-induced obesity (DIO), a two-week intraperitoneal treatment with palmitoylated PrRP lowered food intake by 24% and body weight by 8%. This treatment also improved glucose tolerance and tended to decrease leptin levels and adipose tissue masses in a dose-dependent manner. In contrast, in ZDF rats, the same treatment with palmitoylated PrRP lowered food intake but did not significantly affect body weight or glucose tolerance, probably in consequence of severe leptin resistance due to a nonfunctional leptin receptor. Our data indicate a good efficacy of lipidized PrRP in DIO rats. Thus, the strong anorexigenic, body weight-reducing, and glucose tolerance-improving effects make palmitoylated PrRP an attractive candidate for anti-obesity treatment.


Subject(s)
Body Weight/drug effects , Obesity/drug therapy , Prolactin-Releasing Hormone/analogs & derivatives , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Appetite Depressants/pharmacology , Diabetes Mellitus, Experimental/metabolism , Diet, High-Fat/adverse effects , Drug Design , Eating/drug effects , Glucose Tolerance Test , Lipid Metabolism/drug effects , Lipid Metabolism/genetics , Lipoylation , Liver/drug effects , Liver/metabolism , Male , Mice , Obesity/metabolism , Obesity/pathology , Prolactin-Releasing Hormone/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Rats, Zucker , Receptors, Leptin/deficiency
5.
Peptides ; 75: 109-17, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26643957

ABSTRACT

Obesity is an escalating epidemic, but an effective non-invasive therapy is still scarce. For obesity treatment, anorexigenic neuropeptides are promising tools, but their delivery from the periphery to the brain is complicated by their peptide character. In order to overcome this unfavorable fact, we have applied the lipidization of neuropeptide prolactin-releasing peptide (PrRP), whose strong anorexigenic effect was demonstrated. A palmitoylated analog of human PrRP (h palm-PrRP31) was injected in free-fed Wistar rats by three routes: subcutaneous (s.c.), intraperitoneal (i.p) (both 5 mg/kg) and intravenous (i.v.) (from 0.01 to 0.5 mg/kg). We found a circulating compound in the blood after all three applications with the highest concentration after i.v. administration. This corresponds to the effect on food intake, which was also strongest after i.v. injection. Moreover, this is in agreement with the fact that the expression of c-Fos in specific brain regions involved in food intake regulation was also highest after intravenous application. Pharmacokinetic data are further supported by results obtained from dynamic light scattering and CD spectroscopy. Human palm-PrRP31 analog showed a strong tendency to micellize, and formation of aggregates suggested lower availability after i.p. or s.c. application. We have demonstrated that palm-PrRP influenced food intake even in free fed rats. Not surprisingly, the maximal effect was achieved after the intravenous application even though two orders of magnitude lower dose was used compared to both two other applications. We believe that palm-PrRP could have a potential as an antiobesity drug when its s.c. application would be improved.


Subject(s)
Anti-Obesity Agents/administration & dosage , Energy Intake/drug effects , Peptide Fragments/administration & dosage , Prolactin-Releasing Hormone/analogs & derivatives , Animals , Anti-Obesity Agents/metabolism , Anti-Obesity Agents/pharmacokinetics , Brain/metabolism , CHO Cells , Cricetinae , Cricetulus , Drug Evaluation, Preclinical , Humans , Neurons/drug effects , Neurons/metabolism , Obesity/drug therapy , Peptide Fragments/metabolism , Peptide Fragments/pharmacokinetics , Prolactin-Releasing Hormone/administration & dosage , Prolactin-Releasing Hormone/metabolism , Prolactin-Releasing Hormone/pharmacokinetics , Protein Binding , Proto-Oncogene Proteins c-fos/metabolism , Rats , Receptors, G-Protein-Coupled/metabolism
6.
J Alzheimers Dis ; 45(3): 823-35, 2015.
Article in English | MEDLINE | ID: mdl-25624414

ABSTRACT

Numerous epidemiological and experimental studies have demonstrated that patients who suffer from metabolic disorders, such as type 2 diabetes mellitus (T2DM) or obesity, have higher risks of cognitive dysfunction and of Alzheimer's disease (AD). Impaired insulin signaling in the brain could contribute to the formation of neurofibrillary tangles, which contain an abnormally hyperphosphorylated tau protein. This study aimed to determine whether potential tau hyperphosphorylation could be detected in an obesity-induced pre-diabetes state and whether anorexigenic agents could affect this state. We demonstrated that 6-month-old mice with monosodium glutamate (MSG) obesity, which represent a model of obesity-induced pre-diabetes, had increased tau phosphorylation at Ser396 and Thr231 in the hippocampus compared with the controls, as determined by western blots. Two weeks of subcutaneous treatment with a lipidized analog of prolactin-releasing peptide (palm-PrRP31) or with the T2DM drug liraglutide, which both had a central anorexigenic effect, resulted in increased phosphorylation of the insulin cascade kinases PDK1 (Ser241), Akt (Thr308), and GSK-3ß (Ser9). Furthermore, these drugs attenuated phosphorylation at Ser396, Thr231, and Thr212 of tau and of the primary tau kinases in the hippocampi of 6-month-old MSG-obese mice. We identified tau hyperphosphorylation in the obesity-induced pre-diabetes state in MSG-obese mice and demonstrated the beneficial effects of palm-PrRP31 and liraglutide, both of known central anorexigenic effects, on hippocampal insulin signaling and on tau phosphorylation.


Subject(s)
Flavoring Agents/toxicity , Hippocampus/drug effects , Insulins/metabolism , Lipopeptides/metabolism , Obesity , Signal Transduction/drug effects , Sodium Glutamate/toxicity , tau Proteins/metabolism , Analysis of Variance , Animals , Body Weight/drug effects , Disease Models, Animal , Glucagon-Like Peptide 1/genetics , Glucagon-Like Peptide 1/pharmacology , Glucose Tolerance Test , Hippocampus/metabolism , Lipopeptides/therapeutic use , Male , Mice , Obesity/chemically induced , Obesity/drug therapy , Obesity/pathology , Phosphorylation/drug effects , Prolactin-Releasing Hormone/drug effects , Prolactin-Releasing Hormone/pharmacology , Receptors, G-Protein-Coupled/metabolism , Time Factors
7.
BMC Neurosci ; 15: 111, 2014 Sep 25.
Article in English | MEDLINE | ID: mdl-25257559

ABSTRACT

BACKGROUND: Insulin signaling and Tau protein phosphorylation in the hippocampi of young and old obese Zucker fa/fa rats and their lean controls were assessed to determine whether obesity-induced peripheral insulin resistance and aging are risk factors for central insulin resistance and whether central insulin resistance is related to the pathologic phosphorylation of the Tau protein. RESULTS: Aging and obesity significantly attenuated the phosphorylation of the insulin cascade kinases Akt (protein kinase B, PKB) and GSK-3ß (glycogen synthase kinase 3ß) in the hippocampi of the fa/fa rats. Furthermore, the hyperphosphorylation of Tau Ser396 alone and both Tau Ser396 and Thr231 was significantly augmented by aging and obesity, respectively, in the hippocampi of these rats. CONCLUSIONS: Both age-induced and obesity-induced peripheral insulin resistance are associated with central insulin resistance that is linked to hyperTau phosphorylation. Peripheral hyperinsulinemia, rather than hyperglycemia, appears to promote central insulin resistance and the Tau pathology in fa/fa rats.


Subject(s)
Aging/physiology , Hippocampus/physiopathology , Insulin Resistance/physiology , Insulin/metabolism , Obesity/physiopathology , tau Proteins/metabolism , Animals , Blotting, Western , Glucose Tolerance Test , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Male , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Rats, Zucker , Signal Transduction , tau Proteins/genetics
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