The FOXN3 gene locus is associated with fasting blood glucose levels in nondiabetic human population genetic studies. The blood glucose-modifying variation within this gene regulates the abundance of both FOXN3 protein andtranscript in primary human hepatocytes, with the hyperglycemia risk allelecausing increases in both FOXN3 protein and transcript. Using transgenic andknock-out zebrafish models, we showed previously that FOXN3 is a transcriptional repressor that regulates fasting blood glucose by altering liver geneexpression of MYC, a master transcriptional regulator of glucose utilization,and by modulating pancreatic a cell mass and function through an unknownmechanism. Since homozygous Foxn3 null mice die perinatally, and heterozygous carries of the null allele are smaller than wild-type siblings, we examinethe metabolic effects of decreasing mouse liver Foxn3 expression in adult life,performing dynamic endocrine tests not feasible in adult zebrafish. Fastingglucose, glucagon, and insulin; and dynamic responses to glucose, insulin,pyruvate, glutamine, and glucagon were measured. Gluconeogenic and aminoacid catabolic gene expression was examined in livers, as well. Knocking downliver Foxn3 expression via transduction with adeno-associated virus serotype 8particles encoding a short hairpin RNA targeting Fonx3 decreases fasting glucose and increases Myc expression, without altering fasting glucagon or fastinginsulin. Liver Foxn3 knock-down confers increases glucose tolerance, has noeffect on insulin tolerance or response to glucagon challenge, blunts pyruvateand glutamine tolerance, and modulates expression of amino acid transportersand catabolic enzymes. We conclude that liver Foxn3 regulates substrate selection for gluconeogenesis.

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