Journal article
FOXN3 controls liver glucose metabolism by regulating gluconeogenic substrate selection
Physiological reports, Vol.7(18), pp.e14238-n/a
09/01/2019
DOI: 10.14814/phy2.14238
PMCID: PMC6759504
PMID: 31552709
Abstract
The FOXN3 gene locus is associated with fasting blood glucose levels in non-diabetic human population genetic studies. The blood glucose-modifying variation within this gene regulates the abundance of both FOXN3 protein and transcript in primary human hepatocytes, with the hyperglycemia risk allele causing increases in both FOXN3 protein and transcript. Using transgenic and knock-out zebrafish models, we showed previously that FOXN3 is a transcriptional repressor that regulates fasting blood glucose by altering liver gene expression of MYC, a master transcriptional regulator of glucose utilization, and by modulating pancreatic alpha cell mass and function through an unknown mechanism. Since homozygous Foxn3 null mice die perinatally, and heterozygous carries of the null allele are smaller than wild-type siblings, we examine the metabolic effects of decreasing mouse liver Foxn3 expression in adult life, performing dynamic endocrine tests not feasible in adult zebrafish. Fasting glucose, glucagon, and insulin; and dynamic responses to glucose, insulin, pyruvate, glutamine, and glucagon were measured. Gluconeogenic and amino acid catabolic gene expression was examined in livers, as well. Knocking down liver Foxn3 expression via transduction with adeno-associated virus serotype 8 particles encoding a short hairpin RNA targeting Fonx3 decreases fasting glucose and increases Myc expression, without altering fasting glucagon or fasting insulin. Liver Foxn3 knock-down confers increases glucose tolerance, has no effect on insulin tolerance or response to glucagon challenge, blunts pyruvate and glutamine tolerance, and modulates expression of amino acid transporters and catabolic enzymes. We conclude that liver Foxn3 regulates substrate selection for gluconeogenesis.
Details
- Title: Subtitle
- FOXN3 controls liver glucose metabolism by regulating gluconeogenic substrate selection
- Creators
- Santhosh Karanth - University of UtahBhagirath Chaurasia - University of UtahFaith M. Bowman - University of UtahTrevor S. Tippett - University of UtahWilliam L. Holland - University of UtahScott A. Summers - University of UtahAmnon Schlegel - University of Utah
- Resource Type
- Journal article
- Publication Details
- Physiological reports, Vol.7(18), pp.e14238-n/a
- DOI
- 10.14814/phy2.14238
- PMID
- 31552709
- PMCID
- PMC6759504
- NLM abbreviation
- Physiol Rep
- ISSN
- 2051-817X
- eISSN
- 2051-817X
- Publisher
- Wiley
- Number of pages
- 7
- Grant note
- R56DK111494-01A1 / National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Department of Internal Medicine Diabetes and Metabolism Research Center of the University of Utah P30DK020579 / Pilot & Feasibility Grant from the Washington University Diabetes Research Center R01DK108833 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) University of Utah Molecular Medicine Program
- Language
- English
- Date published
- 09/01/2019
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359675402771
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