title: Vitamin B12 conjugation of peptide-YY(3-36) decreases food intake compared to native peptide-YY(3-36) upon subcutaneous administration in male rats.
abstract: 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-PYYC36 (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 pumps. Increases in hindbrain Fos expression were comparable 90 minutes after B12-PYY(3-36) or PYY3-36 injection relative to saline or B12-PYYC36. Food intake was reduced during a 5-day treatment for both B12-PYY(3-36)- (24%, P = .001) and PYY(3-36)-(13%, P = .008) treated groups relative to baseline. In addition, reduction of food intake after the three dark cycle treatment pulses was more consistent with B12-PYY(3-36) treatment (-26%, -29%, -27%) compared with the PYY(3-36) treatment (-3%, -21%, -16%), and B12-PYY(3-36) generated a significantly longer inhibition of food intake vs. PYY(3-36) treatment after the first two pulses (P = .041 and P = .036, respectively). These findings demonstrate a stronger, more consistent, and longer inhibition of food intake after the pulses of B12-PYY(3-36) conjugate compared with the native PYY(3-36).
authors: Department of Chemistry (K.E.H., R.M.B., R.P.D.), Center for Science and Technology, Syracuse University, Syracuse, New York 13244; Center for Integrative Brain Research (C.T.E., C.L.R.), Division of Endocrinology, Seattle Children's Research Institute, Seattle, Washington 98101; Departments of Medicine (O.G.C., G.G.H., R.P.D.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Research and Development Service (J.E.B.), Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108; Department of Medicine (J.E.B.), Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, Washington 98195; and Division of Endocrinology (C.L.R.), Department of Pediatrics, University of Washington, Seattle, Washington 98105.
authors: Kelly E
authors: KE
authors: Henry
authors: Clinton T
authors: CT
authors: Elfers
authors: Rachael M
authors: RM
authors: Burke
authors: Oleg G
authors: OG
authors: Chepurny
authors: George G
authors: GG
authors: Holz
authors: James E
authors: JE
authors: Blevins
authors: Christian L
authors: CL
authors: Roth
authors: Robert P
authors: RP
authors: Doyle
mesh_terms: D000818:Animals; D004337:Drug Carriers; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D055104:Infusions, Subcutaneous; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D019894:Peptide YY / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000819:agonists*; D014805:Vitamin B 12; D014803:Vitamin B Complex
chemical_list: D004337:Drug Carriers; D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D019894:Peptide YY; D014803:Vitamin B Complex; C061785:peptide YY (3-36); D014805:Vitamin B 12