A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose

Santhosh Karanth, J. D. Adams, Maria de los Angeles Serrano, Ezekiel B. Quittner-Strom, Judith Simcox, Claudio J. Villanueva, Lale Ozcan, William L. Holland, H. Joseph Yost, Adrian Vella, Amnon Schlegel

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


The common genetic variation at rs8004664 in the FOXN3 gene is independently and significantly associated with fasting blood glucose, but not insulin, in non-diabetic humans. Recently, we reported that primary hepatocytes from rs8004664 hyperglycemia risk allele carriers have increased FOXN3 transcript and protein levels and liver-limited overexpression of human FOXN3, a transcriptional repressor that had not been implicated in metabolic regulation previously, increases fasting blood glucose in zebrafish. Here, we find that injection of glucagon into mice and adult zebrafish decreases liver Foxn3 protein and transcript levels. Zebrafish foxn3 loss-of-function mutants have decreased fasting blood glucose, blood glucagon, liver gluconeogenic gene expression, and α cell mass. Conversely, liver-limited overexpression of foxn3 increases α cell mass. Supporting these genetic findings in model organisms, non-diabetic rs8004664 risk allele carriers have decreased suppression of glucagon during oral glucose tolerance testing. By reciprocally regulating each other, liver FOXN3 and glucagon control fasting glucose.

Original languageEnglish (US)
Pages (from-to)312-319
Number of pages8
JournalCell reports
Issue number2
StatePublished - Jul 10 2018


  • FOXN3
  • fasting metabolism
  • glucagon
  • human
  • mouse
  • type 2 diabetes mellitus
  • zebrafish
  • α cell

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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