Potent antiobesity effect of a short-length peptide YY-analogue continuously administered in mice.

The gastrointestinal peptide, peptide YY3-36 (PYY3-36) and its shorter peptide analogues have been reported to reduce appetite by activating the neuropeptide Y2 receptor (Y2R), which is associated with obesity and other metabolic diseases. A 14-amino acid PYY analogue, Ac-[d-Pro24,Cha27,28,36,Aib31]PYY(23-36) (3), showed high binding affinity and agonist activity for the Y2R, similar to that of PYY3-36, but had weak anorectic activity upon continuous administration in lean mice. Three amino acid substitutions [Pya(4)26, Aib28, Lys30], which contributed to the decreased hydrophobicity of 3, efficiently increased its anorectic activity. The compound containing these three amino acids, Ac-[d-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23-36) (22), exerted more potent and durable food intake suppression than that by PYY3-36 in lean mice, as well as excellent Y2R agonist activity (EC50: 0.20nM) and good subcutaneous bioavailability (66.6%). The 11-day continuous administration of 22 at 1mg/kg/day successfully produced antiobese and antidiabetic effects, with more than 20% body weight loss in obese and Type 2 diabetes ob/ob model mice.

Highly potent antiobesity effect of a short-length peptide YY analog in mice.

Continuous administration of a 14-amino acid peptide YY (PYY) analog, Ac-[d-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23-36) (4), which has a high binding affinity and agonist activity for the neuropeptide Y2 receptor (Y2R), has previously shown an antiobesity effect in a 2-week diet-induced obesity (DIO) study in mice. However, there remained a possibility to obtain more potent analogs by further improving its pharmacokinetic profile. A combination of the N-terminal 4-imidazolecarbonyl moiety and three amino acid substitutions, trans-4-hydroxy-d-proline (d-Hyp)24, isovaline (Iva)25, and γ-methylleucine (γMeLeu)28, not only improved the binding affinity of the peptide for Y2R but also increased its anorectic activity in lean mice. In a 2-week DIO study in mice, continuous administration of 4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23-36) (31, PYY-1119) at a dose of 0.03mg/kg/day showed a highly potent antiobesity effect, with more than 10% body weight reduction.

Early Life Stress-Induced Epigenetic Programming of Hippocampal NPY-Y2 Receptor Gene Expression Changes in Response to Adult Stress.

Early Life Stress (ELS) can critically influence brain development and future stress responses and thus represents an important risk factor for mental health and disease. Neuropeptide Y (NPY) is discussed to be a key mediator of resilient vs. vulnerable adaptations and specifically, the NPY-Y2 receptor (Y2R) may be involved in the pathophysiology of depression due to its negative regulation of NPY-release. The present study addressed the hypotheses that ELS and adult stress (AS) affect the expression of hippocampal Y2R and that exposure to ELS induces an epigenetically mediated programming effect towards a consecutive stress exposure in adulthood. The specific aims were to investigate if (i) ELS or AS as single stressors induce changes in Y2 receptor gene expression in the hippocampus, (ii) the predicted Y2R changes are epigenetically mediated via promoter-specific DNA-methylation, (iii) the ELS-induced epigenetic changes exert a programming effect on Y2R gene expression changes in response to AS, and finally (iv) if the predicted alterations are sex-specific. Animals were assigned to the following experimental groups: (1) non-stressed controls (CON), (2) only ELS exposure (ELS), (3) only adult stress exposure (CON+AS), and (4) exposure to ELS followed by AS (ELS+AS). Using repeated maternal separation in mice as an ELS and swim stress as an AS we found that both stressors affected Y2R gene expression in the hippocampus of male mice but not in females. Specifically, upregulated expression was found in the CON+AS group. In addition, exposure to both stressors ELS+AS significantly reduced Y2R gene expression when compared to CON+AS. The changes in Y2R expression were paralleled by altered DNA-methylation patterns at the Y2R promoter, specifically, a decrease in mean DNA-methylation in the CON+AS males compared to the non-AS exposed groups and an increase in the ELS+AS males compared to the CON+AS males. Also, a strong negative correlation of mean DNA-methylation with Y2R expression was found. Detailed CpG-site-specific analysis of DNA-methylation revealed that ELS induced increased DNA-methylation only at specific CpG-sites within the Y2R promoter. It is tempting to speculate that these ELS-induced CpG-site-specific changes represent a "buffering" programming effect against elevations of Y2R expression induced by AS.

Neuropeptide Y Y2 and Y5 receptors as potential targets for neuroprotective and antidepressant therapies: Evidence from preclinical studies.

There is currently no effective treatment either for neurological illnesses (ischemia and neurodegenerative diseases) or psychiatric disorders (depression), in which the Glu/GABA balance is disturbed and accompanied by significant excitotoxicity. Therefore, the search for new and effective therapeutic strategies is imperative for these disorders. Studies conducted over the last several years indicate that the neuropeptide Y (NPY)-ergic system may be a potential therapeutic target for neuroprotective or antidepressant compounds. This review focuses on the neuroprotective roles of Y2 and Y5 receptors (YRs) in neurological disorders such as ischemia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and in psychiatric disorders such as depression. It summarizes current knowledge on the possible mechanisms underlying the neuroprotective or antidepressant-like actions of Y2R and Y5R ligands. The review also discusses ligands acting at Y2R and Y5R and their limitations as in vivo pharmacological tools. The results from the preclinical studies discussed here may be useful in developing effective therapeutic strategies to treat neurological diseases on the one hand and psychiatric disorders on the other, and may pave the way for the development of novel Y2R and Y5R ligands as candidate drugs for the treatment of these diseases.

Antiobesity Effect of a Short-Length Peptide YY Analogue after Continuous Administration in Mice.

Gastrointestinal peptides such as peptide YY (PYY) can regulate appetite, which is relevant to the study of obesity. The intraperitoneal bolus administration of PYY3-36 and a 12-amino acid PYY analogue, benzoyl-[Cha27,28,36,Aib31]PYY25-36 (1), showed similar anorectic activity by activating the Y2 receptor (Y2R). However, food intake inhibition and body weight loss were not observed upon continuous subcutaneous administration of 1 with osmotic pumps in diet-induced obese (DIO) mice. N-Terminal elongation of 1, together with amino acid substitution at position 24, led to a hydrophilic 14-amino acid peptide, Ac-[d-Hyp24,Cha27,28,36,Aib31]PYY23-36 (18), that showed higher affinity and more potent agonist activity for Y2R and a robust anorectic activity with potency similar to that of PYY3-36. In addition, the continuous subcutaneous administration of 18 at 0.3 mg/(kg·day) induced significant body weight loss in DIO mice. These results suggest that a short-length PYY analogue can be a lead compound for antiobesity therapy in a sustained-release formulation.