title: Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding.
abstract: Fibroblast growth factor (FGF)21 is an endocrine hormone that is expressed in multiple tissues and functions physiologically to maintain energy homeostasis. FGF21 is being pursued as a therapeutic target for diabetes and obesity because of its rapid and potent effects on improving insulin sensitivity. However, whether FGF21 enhances insulin sensitivity under physiologic conditions remains unclear. Here, we show that liver-derived FGF21 enters the circulation during fasting but also remains present and functional during the early stage of refeeding. After a prolonged fast, FGF21 acts as an insulin sensitizer to overcome the peripheral insulin resistance induced by fasting, thereby maximizing glucose uptake. Likewise, FGF21 is produced from the liver during overfeeding and mitigates peripheral insulin resistance. DIO FGF21 liver-specific knockout, but not FGF21 adipose-specific knockout, mice have increased insulin resistance and decreased brown adipose tissue-mediated glucose disposal. These data are compatible with the concept that FGF21 functions physiologically as an insulin sensitizer under conditions of acute refeeding and overfeeding.
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Markan
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA.
authors.forename: Meghan C
authors.initials: MC
authors.lastname: Naber
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA.
authors.forename: Magdalene K
authors.initials: MK
authors.lastname: Ameka
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA.
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Anderegg
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, NY.
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA matthew-potthoff@uiowa.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Potthoff
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D005215:Fasting / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001786:Blood Glucose; D007328:Insulin; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005947:Glucose