Introduction: Anti-obesity drugs with increased efficacy and safety are urgently being sought. Peptide YY336 (PYY336) is an attractive drug target due to its anorectic effect and decreased circulation concentration, without drug resistance, in obese individuals. Its short half-life and required method of delivery are limiting factors in its clinical application. Transport and uptake mechanisms, including blood-brain barrier passage, of vitamin B12 (B12) is highly efficient in mammals. We tested the hypothesis that conjugation of B12PYY336 will help to overcome major hurdles of PYY336 by improved efficacy and pharmacokinetics.
Methods: B12PYY336 conjugate was tested against native PYY336, and an inactive B12PYYC36 (null control) on food intake, weight gain and peptide concentrations in lean male SpragueDawley rats (SD 9 weeks, mean weight 316 g) as well as genetic obese diabetic Zucker rats (ZD, mean weight 891 g). Daily treatments were delivered subcutaneously in five 1-h pulses, each pulse delivering 510 nmol/kg, by implanted micro-infusion pumps.
Results: In SD rats, food intake was reduced during 5-day treatment by 24% in B12PYY336 and by 13% in PYY336 treated groups relative to baseline. B12PYY336 generated a significantly longer inhibition of food intake vs PYY336 treatment following the first two pulses (121 min vs 81 min, P<0.05). In ZD rats, food intake was reduced by 22.5% during 4 days of treatment with B12PYY336 vs 13% during PYY336 (P=0.012 and 0.031 respectively). After 4 days of treatment, body weight was reduced by 10 g in B12PYY336 (P=0.049) vs 4 g in PYY336 treated ZD rats. Pharmacokinetic parameters showed positive effects of B12 conjugation on volume of distribution, clearance, and improved half-life (1.4 h vs 0.8 h, B12PYY336 vs PYY336).
Conclusion: Our data demonstrate for the first time that conjugation of B12PYY336 improved pharmacology, resulting in greater suppression of food intake and body weight in lean and obese rat models.
Funding: Sources of research support: NIH R15DK097675-01A1 and support from W M Wrigley Jr company, Chicago, IL, USA.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology