{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T08:32:43Z","timestamp":1648801963674},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T00:00:00Z","timestamp":1561680000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Binational Agricultural Research and Development Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic energy insufficiency resulting from inadequate feed intake or increased nutrient demand reduces plasma leptin in ruminants. Treatment of energy-deficient ruminants with exogenous leptin has identified some physiological consequences of reduced plasma leptin, but their full complement remains unknown. Additional leptin-dependent responses could be identified by using strategies that interfere with leptin signaling such as administration of leptin mutants that act as competitive antagonists. The effectiveness of these antagonists depends on their fold excess over endogenous leptin, and this condition can be achieved under in vivo conditions by extending the half-life (t1\/2) of the antagonist by addition of a polyethylene glycol (PEG) molecule (pegylation). Use of this approach in ruminants, however, is limited by the lack of information on the t1\/2 of native and pegylated leptin and on the most effective route of administration. To answer these questions, newborn lambs (n = 3) were injected with an intravenous (i.v.) bolus of 150 \u00b5g of human leptin followed by blood sampling over the next 12 h. Analysis of the semilog plasma leptin concentration over time yielded a t1\/2 of 43 \u00b1 4.9 min; an i.v. bolus of 276 \u00b5g of bovine leptin yielded a comparable t1\/2 (P &gt; 0.05). Next, newborn lambs (n = 4) received a single dose of 229 \u03bcg\/kg of metabolic body weight (BW0.75) of pegylated super human leptin antagonist (PEG-SHLA) via the i.v. or subcutaneous (s.c.) route. Plasma PEG-SHLA concentration reached a peak of 1,528 \u00b1 78 ng\/mL after 1 min and a nadir of 71 \u00b1 9 ng\/mL after 24 h with the i.v. route versus a peak of 423 \u00b1 43 ng\/mL after 300 min and a nadir of 146 \u00b1 22 ng\/mL after 24 h for the s.c. route; the t1\/2 of PEG-SHLA was 394 \u00b1 29 min for the i.v. route and 433 \u00b1 58 min for the s.c. route. Finally, plasma concentration of PEG-SHLA was modeled when given either i.v. or s.c. at a dose of 229 \u03bcg\/kg BW0.75 every 12 h. Once a steady state was reached, peak and lowest concentrations PEG-SHLA over the 12-h windows were 2,269 and 403 ng\/mL for the i.v. route and 814 and 555 ng\/mL for the s.c. route. Weighted PEG-SHLA concentrations over the 12-h period were 1,455 and 713 ng\/mL for the i.v. and s.c. route, translating into 364- and 178-fold excess over endogenous plasma leptin. These data confirm the effectiveness of pegylation in extending the t1\/2 of leptin antagonists in newborn lambs and in increasing their circulation in fold excess over endogenous leptin.<\/jats:p>","DOI":"10.1093\/jas\/skz218","type":"journal-article","created":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T05:12:37Z","timestamp":1561698757000},"page":"3768-3775","source":"Crossref","is-referenced-by-count":1,"title":["Technical note: Effects of pegylation and route of administration on leptin kinetics in newborn lambs1"],"prefix":"10.1093","volume":"97","author":[{"given":"Jose M","family":"Ramos-Nieves","sequence":"first","affiliation":[{"name":"Department of Animal Science, Cornell University, Ithaca, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah L","family":"Giesy","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Cornell University, Ithaca, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne S","family":"Schwark","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arieh","family":"Gertler","sequence":"additional","affiliation":[{"name":"The Robert H. 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