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
Affiliations
Santhosh Karanth
University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT, USA
J.D. Adams
Department of Internal Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, USA
Maria de los Angeles Serrano
University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT, USA
Ezekiel B. Quittner-Strom
University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA
Judith Simcox
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
Claudio J. Villanueva
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
Lale Ozcan
Department of Medicine, Division of Molecular Medicine, Columbia University Medical Center, New York, NY, USA
William L. Holland
University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
H. Joseph Yost
University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA
Adrian Vella
Department of Internal Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, USA
Amnon Schlegel
University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA; Corresponding author
Summary: 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. : 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. Keywords: FOXN3, glucagon, α cell, fasting metabolism, type 2 diabetes mellitus, human, mouse, zebrafish
