Circulating FGF21 is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding

  1. Matthew J. Potthoff1,2*
  1. 1Departments of Pharmacology and
  2. 2Fraternal Order of Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA;
  3. 3Department of Pharmacology,
  4. 4Howard Hughes Medical Institute, and
  5. 5Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
  6. 6Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA;
  1. Corresponding author: Matthew J. Potthoff, Email: matthew-potthoff{at}


Fibroblast growth factor 21 (FGF21) 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. Following 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. Diet-induced obese 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.


  • equal contributions

  • Received April 11, 2014.
  • Accepted July 2, 2014.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details.