Background/ObjectivesProlactin-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/MethodsThe 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.ResultsAt 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.ConclusionsWe 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.
The situation following anti-obesity drug termination is rarely investigated, eventhough a decrease in body weight needs to be sustained. Therefore, this study examined the impact of twice-daily peripheral administration of 5 mg/kg [N-palm-γGlu-Lys] prolactin-releasing peptide 31 (palm-PrRP31) in mice with diet-induced obesity (DIO from consuming a high-fat diet) after 28 days of treatment (palm-PrRP31 group) and after 14 days of peptide treatment followed by 14 days of discontinuation (palm-PrRP31 + saline group). At the end of the treatment, cumulative food intake, body weight and subcutaneous fat weight/body weight ratio and leptin plasma level were reduced significantly in both the palm-PrRP31 group and the palm-PrRP31 + saline group compared to the saline control group. This reduction correlated with significantly increased FOSB, a marker of long-term neuronal potentiation, in the nucleus arcuatus and nucleus tractus solitarii, areas known to be affected by the anorexigenic effect of palm-PrRP31. Moreover, activation of leptin-related hypothalamic signaling was registered through an increase in phosphoinositide-3-kinase, increased phosphorylation of protein kinase B (PKB, AKT) and enhanced extracellular signal-regulated kinase 1/2 phosphorylation. Besides, lowered apoptotic markers c-JUN N-terminal kinase and c-JUN phosphorylation were registered in the hypothalami of both palm-PrRP31-treated groups. This study demonstrates that palm-PrRP31 positively affects feeding and leptin-related hypothalamic signaling, not only after 28 days of treatment but even 14 days after the termination of a 14-day long treatment without the yo-yo effect.
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.
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