@article{ddad4273f6364960a2f484870d2b76a2,
title = "A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose",
abstract = "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.",
keywords = "FOXN3, fasting metabolism, glucagon, human, mouse, type 2 diabetes mellitus, zebrafish, α cell",
author = "Santhosh Karanth and Adams, {J. D.} and Serrano, {Maria de los Angeles} and Quittner-Strom, {Ezekiel B.} and Judith Simcox and Villanueva, {Claudio J.} and Lale Ozcan and Holland, {William L.} and Yost, {H. Joseph} and Adrian Vella and Amnon Schlegel",
note = "Funding Information: This study was supported by NIH grants R01DK096710 and R56DK111494 (to A.S.), R01DK078646 and R01DK116231 (to A.V.), UM1HL098160 (to H.J.Y.), R01DK112826 (to W.L.H.), R01DK106045 (to L.O.), R01DK103930 (to C.J.V.), T32DK091317 (to J.S.), and T32DK007352 (to J.D.A.); JDRF award SRA-2016-149-Q-R (to W.L.H.); the Driving Out Diabetes – A Larry H. Miller Family Wellness Initiative postdoctoral fellowship (to S.K.); and funds from the University of Utah Molecular Medicine Program (to A.S.) and the Utah Diabetes and Metabolism Research Center (to A.S). Human studies were performed in the Mayo Clinic General Clinical Research Center (supported by UL1TR000135 from NIH ; PI, Sundeep Khosla). We thank Wenbiao Chen for sharing animals and Scott Summers and Bhagirath Chaurasia for their comments and advice. Funding Information: This study was supported by NIH grants R01DK096710 and R56DK111494 (to A.S.), R01DK078646 and R01DK116231 (to A.V.), UM1HL098160 (to H.J.Y.), R01DK112826 (to W.L.H.), R01DK106045 (to L.O.), R01DK103930 (to C.J.V.), T32DK091317 (to J.S.), and T32DK007352 (to J.D.A.); JDRF award SRA-2016-149-Q-R (to W.L.H.); the Driving Out Diabetes ? A Larry H. Miller Family Wellness Initiative postdoctoral fellowship (to S.K.); and funds from the University of Utah Molecular Medicine Program (to A.S.) and the Utah Diabetes and Metabolism Research Center (to A.S). Human studies were performed in the Mayo Clinic General Clinical Research Center (supported by UL1TR000135 from NIH; PI, Sundeep Khosla). We thank Wenbiao Chen for sharing animals and Scott Summers and Bhagirath Chaurasia for their comments and advice. Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = jul,
day = "10",
doi = "10.1016/j.celrep.2018.06.039",
language = "English (US)",
volume = "24",
pages = "312--319",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}