Details

Autor(en) / Beteiligte

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

Titel

A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose

Ist Teil von

• Cell reports (Cambridge), 2018-07, Vol.24 (2), p.312-319

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Glucagon lowers FOXN3 expression in liver•Deletion of FOXN3 lowers fasting blood glucose in zebrafish•Deletion of FOXN3 decreases the number of α cells in the endocrine pancreas•The FOXN3 hyperglycemia risk allele blunts glucagon suppression during glucose challenge Karanth et al. find that glucagon lowers liver expression of Foxn3. Deletion of the Foxn3 gene decreases fasting blood glucose and the number of glucagon-producing α cells in the primary islet of zebrafish. Human carriers of the hyperglycemia risk allele of FOXN3 gene fail to suppress glucagon during oral glucose challenge.