ZFIN ID: ZDB-PUB-180713-10
A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose
Karanth, S., Adams, J.D., Serrano, M.L.A., Quittner-Strom, E.B., Simcox, J., Villanueva, C.J., Ozcan, L., Holland, W.L., Yost, H.J., Vella, A., Schlegel, A.
Date: 2018
Source: Cell Reports   24: 312-319 (Journal)
Registered Authors: Karanth, Santhosh, Schlegel, Amnon, Yost, H. Joseph
Keywords: FOXN3, fasting metabolism, glucagon, human, mouse, type 2 diabetes mellitus, zebrafish, α cell
MeSH Terms:
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Animals
  • Base Sequence
  • Blood Glucose/metabolism
  • Child
  • Fasting/blood
  • Fasting/metabolism*
  • Forkhead Transcription Factors/genetics
  • Forkhead Transcription Factors/metabolism*
  • Gene Expression Regulation
  • Glucagon/metabolism*
  • Gluconeogenesis/genetics
  • Glucose/metabolism*
  • Glucose Tolerance Test
  • Hepatocytes/metabolism*
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Mutation/genetics
  • Polymorphism, Single Nucleotide/genetics
  • Signal Transduction
  • Young Adult
  • Zebrafish/genetics
PubMed: 29996093 Full text @ Cell Rep.
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.