Fibroblast growth factor-21 (FGF21) administration to early-lactating dairy cows. II. Pharmacokinetics, whole-animal performance, and lipid metabolism

L. S. Caixeta, S. L. Giesy, C. S. Krumm, J. W. Perfield, A. Butterfield, Y. R. Boisclair

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Dairy cows cope with severe energy insufficiency in early lactation by engaging in intense and sustained mobilization of fatty acids from adipose tissue. An unwanted side effect of this adaptation is excessive lipid accumulation in the liver, which in turn impairs hepatic functions. Mice experiencing increased hepatic fatty acid flux are protected from this condition through coordinated actions of the newly described hormone fibroblast growth factor-21 (FGF21) on liver and adipose tissue. The possibility of an analogous role for FGF21 in dairy cows is suggested by its rapid increase in plasma levels around parturition followed by chronically elevated levels in the first few weeks of lactation. To test this hypothesis, dairy cows were randomly assigned on d 12.6 ± 2.2 (± standard error) of lactation to receive either an excipient (control; n = 6) or recombinant human FGF21 (n = 7), first as an FGF21 bolus of 3 mg/kg of body weight (BW) followed 2 d later by a constant i.v. infusion of FGF21 at a rate of 6.3 mg/kg of metabolic BW for 9 consecutive days. After bolus administration, human FGF21 circulated with a half-life of 194 min, and its constant infusion increased total plasma concentration 117-fold over levels in excipient-infused cows. The FGF21 treatment had no effect on voluntary feed intake, milk yield, milk energy output, or net energy balance measured over the 9-d infusion or on final BW. Plasma fatty acids circulated at lower concentrations in the FGF21 group than in the control group for the 8-h period following bolus administration, but this reduction was not significant during the period of constant i.v. infusion. Treatment with FGF21 caused a 50% reduction in triglyceride content in liver biopsies taken at the end of the constant i.v. infusion without altering the mRNA abundance of key genes involved in the transport, acyl coenzyme A activation, or oxidation of fatty acids. In contrast, FGF21 treatment ablated the recovery of plasma insulin-like growth factor-1 seen in control cows during the 9-d i.v. infusion period despite a tendency for higher plasma growth hormone. This effect was associated with increased hepatic mRNA abundance of the intracellular inhibitor of growth hormone receptor trafficking, LEPROT. Overall, these data confirm the ability of FGF21 to reduce lipid accumulation in bovine liver and suggest the possibility that FGF21 does so by attenuating the hepatic influx of adipose tissue-derived fatty acids.

Original languageEnglish (US)
Pages (from-to)11597-11608
Number of pages12
JournalJournal of Dairy Science
Volume102
Issue number12
DOIs
StatePublished - Dec 2019
Externally publishedYes

Bibliographical note

Funding Information:
This material is based on work that is supported by the National Institute of Food and Agriculture, USDA (Washington, DC), under award number 2010-65206-20683 and Hatch/Multistate projects under 1000962 and 1017053. A. Butterfield and J. W. Perfield II are paid employees of Eli Lilly and Company (Indianapolis, IN) and may own company stock or possess stock options. We thank Alexei Kharitonenkov (Novo Nordisk Research Center Indianapolis, Indianapolis, IN) for his interest in and support of this project. We also thank Katie M. Schoenberg (Elanco Animal Health, Greenfield, IN) for helpful discussion, Phillip Gondim for assisting with the animal work, Brittany L. Moore (Cornell University, Ithaca, NY) for performing metabolite assays, and Paul L. Milligan (Eli Lilly and Company, Indianapolis, IN) for assistance with the lipidomics analysis.

Funding Information:
This material is based on work that is supported by the National Institute of Food and Agriculture, USDA (Washington, DC), under award number 2010-65206-20683 and Hatch/Multistate projects under 1000962 and 1017053. A. Butterfield and J. W. Perfield II are paid employees of Eli Lilly and Company (Indianapolis, IN) and may own company stock or possess stock options. We thank Alexei Kharitonenkov (Novo Nordisk Research Center Indianapolis, Indianapolis, IN) for his interest in and support of this project. We also thank Katie M. Schoenberg (Elanco Animal Health, Greenfield, IN) for helpful discussion, Phillip Gondim for assisting with the animal work, Brittany L. Moore (Cornell University, Ithaca, NY) for performing metabolite assays, and Paul L. Milligan (Eli Lilly and Company, Indianapolis, IN) for assistance with the lipidomics analysis.

Publisher Copyright:
© 2019 American Dairy Science Association

Keywords

  • fatty acid
  • growth hormone resistance
  • insulin-like growth factor-1
  • liver
  • β-hydroxybutyrate

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