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Challenges to peptide-based therapies include rapid clearance, ready degradation by hydrolysis/proteolysis, and poor intestinal uptake and/or a need for blood brain barrier transport. This work evaluates the efficacy of conjugation of vitamin B₁₂ (B₁₂) on sc administered peptide tyrosine tyrosine (PYY)_3–36 function. In the current experiments, a B₁₂-PYY_3–36 conjugate was tested against native PYY_3–36, and an inactive conjugate B₁₂-PYY_C36 (null control) in vitro and in vivo. In vitro experiments demonstrated similar agonism for the neuropeptide Y2 receptor by the B₁₂-PYY_3–36 conjugate (EC₅₀ 26.5 nM) compared with native PYY_3–36 (EC₅₀ 16.0 nM), with the null control having an EC₅₀ of 1.8 μM. In vivo experiments were performed in young adult male Sprague Dawley rats (9 wk). Daily treatments were delivered sc in five 1-hour pulses, each pulse delivering 5–10 nmol/kg, by implanted microinfusion …