Novel Y2 Receptor Agonist has differential anorectic effects when administered via bolus injection and continuous infusion: Implications for dosing strategies

Klara Hostomska, Victoria Salem, Samar Ghourab, Melisande Addison, Joyceline Shillito, James Minnion, Kevin Murphy, Mohammad Ghatei, Stephen Bloom. Imperial College, London, United Kingdom.

Obesity is a global epidemic and is associated with increased morbidity and mortality. Current treatments are impractical or ineffective. Gut hormones offer a novel target for obesity pharmacotherapy. Endogenous Peptide Tyrosine-Tyrosine (PYY) is a potent appetite inhibiting hormone released from the intestines after ingestion of a meal. Its active form, PYY (3-36), activates inhibitory Y2 receptors in the brain to elicit its anorectic effects. However, PYY (3-36) has a short half life that limits its potential therapeutic use. Through targeted amino acid substitutions, we designed an analogue of PYY (3-36), designated IC59, which has a high affinity for the Y2 receptor and persists longer in the circulation than native PYY (3-36) following subcutaneous administration. Acute subcutaneous administration of IC59 (500nmol/kg) to overnight fasted C57BL/6 mice (n=9) potently reduced 48 hour food intake by 38% compared to saline controls. PYY (3-36) (500nmol/kg) reduced food intake by only 1.4% over the same period. Following these acute studies, investigation of continuous administration of IC59 and PYY (3-36) via Alzet osmotic minipump in C57BL/6 mice for 48 hours was undertaken. Surprisingly, we found that infusion of IC59 (250nmol/kg/day) reduced 48 hour food intake by 10%, whereas as PYY (3-36) (250nmol/kg/day) reduced food intake by 50%. Following the low efficacy of continuous administration of IC59, we examined the effect of daily injection in a model of diet induced obesity. Daily subcutaneous administration of IC59 (500nmol/kg) for 7 days in C57BL/6 mice reduced food intake by 30% and body weight by 8% compared to only 10% and 2% with PYY (3-36), (500nmol/kg), respectively. PYY (3-36) has a short half life and these data suggest prolonged administration increases the biological response. In addition, the relatively reduced performance of IC59 when delivered continuously via Alzet pump might also indicate that there may be alternative mechanisms of action contributing to the effects on food intake. Further work is underway to elucidate the mechanism of action and ideal dosing strategy for IC59.