Vitamin B12 conjugation of peptide-YY3-36 decreases food intake compared to native peptide-YY3-36 upon subcutaneous administration in male rats

Kelly E. Henry, Clinton T. Elfers, Rachael M. Burke, Oleg G. Chepurny, George G. Holz, James E. Blevins, Christian L. Roth, Robert Patrick Doyle

Research output: Contribution to journalArticle

16 Citations (Scopus)

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-PYY3-36 conjugate was tested against native PYY3-36, 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-PYY3-36 conjugate (EC50 26.5nM)comparedwith nativePYY3-36 (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-PYY3-36 or PYY3-36 injection relative to saline or B12-PYYC36. Food intake was reduced during a 5-day treatment for both B12-PYY3-36- (24%, P = .001) and PYY3-36-(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-PYY3-36 treatment (-26%, -29%, -27%) compared with the PYY3-36 treatment (-3%, -21%, -16%), and B12-PYY3-36 generated a significantly longer inhibition of food intake vs PYY3-36 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-PYY3-36 conjugate compared with the native PYY3-36.

Original languageEnglish (US)
Pages (from-to)1739-1749
Number of pages11
JournalEndocrinology
Volume156
Issue number5
DOIs
StatePublished - May 1 2015

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Vitamin B 12
Eating
tyrosyltyrosine
Therapeutics
Rhombencephalon
peptide YY (3-36)
Blood-Brain Barrier
Proteolysis
Sprague Dawley Rats
Young Adult
Hydrolysis
Peptides
Injections

ASJC Scopus subject areas

  • Endocrinology

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Vitamin B12 conjugation of peptide-YY3-36 decreases food intake compared to native peptide-YY3-36 upon subcutaneous administration in male rats. / Henry, Kelly E.; Elfers, Clinton T.; Burke, Rachael M.; Chepurny, Oleg G.; Holz, George G.; Blevins, James E.; Roth, Christian L.; Doyle, Robert Patrick.

In: Endocrinology, Vol. 156, No. 5, 01.05.2015, p. 1739-1749.

Research output: Contribution to journalArticle

Henry, Kelly E. ; Elfers, Clinton T. ; Burke, Rachael M. ; Chepurny, Oleg G. ; Holz, George G. ; Blevins, James E. ; Roth, Christian L. ; Doyle, Robert Patrick. / Vitamin B12 conjugation of peptide-YY3-36 decreases food intake compared to native peptide-YY3-36 upon subcutaneous administration in male rats. In: Endocrinology. 2015 ; Vol. 156, No. 5. pp. 1739-1749.
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AU - Henry, Kelly E.

AU - Elfers, Clinton T.

AU - Burke, Rachael M.

AU - Chepurny, Oleg G.

AU - Holz, George G.

AU - Blevins, James E.

AU - Roth, Christian L.

AU - Doyle, Robert Patrick

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