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

Abstract The gastrointestinal peptide, peptide YY 3–36 (PYY 3–36 ) 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 -Pro 24 ,Cha 27,28,36 ,Aib 31 ]PYY(23–36) ( 3 ), showed high binding affinity and agonist activity for the Y2R, similar to that of PYY 3–36 , but had weak anorectic activity upon continuous administration in lean mice. Three amino acid substitutions [Pya(4) 26 , Aib 28 , Lys 30 ], which contributed to the decreased hydrophobicity of 3 , efficiently increased its anorectic activity. The compound containing these three amino acids, Ac-[ d -Pro 24 ,Pya(4) 26 ,Cha 27,36 ,Aib 28,31 ,Lys 30 ]PYY(23–36) ( 22 ), exerted more potent and durable food intake suppression than that by PYY 3–36 in lean mice, as well as excellent Y2R agonist activity (EC 50 : 0.20 nM) and good subcutaneous bioavailability (66.6%). The 11-day continuous administration of 22 at 1 mg/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.