Antiobesity Effect of a Short-Length Peptide YY Analogue after Continuous Administration in Mice
2017-05-01T00:00:00Z (GMT) by
Gastrointestinal peptides such as peptide YY (PYY) can regulate appetite, which is relevant to the study of obesity. The intraperitoneal bolus administration of PYY<sub>3–36</sub> and a 12-amino acid PYY analogue, benzoyl-[Cha<sup>27,28,36</sup>,Aib<sup>31</sup>]PYY<sub>25–36</sub> (<b>1</b>), 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 <b>1</b> with osmotic pumps in diet-induced obese (DIO) mice. N-Terminal elongation of <b>1</b>, together with amino acid substitution at position 24, led to a hydrophilic 14-amino acid peptide, Ac-[d-Hyp<sup>24</sup>,Cha<sup>27,28,36</sup>,Aib<sup>31</sup>]PYY<sub>23–36</sub> (<b>18</b>), that showed higher affinity and more potent agonist activity for Y2R and a robust anorectic activity with potency similar to that of PYY<sub>3–36</sub>. In addition, the continuous subcutaneous administration of <b>18</b> 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.