A Mutant Allele Encoding DNA Binding–Deficient FoxO1 Differentially Regulates Hepatic Glucose and Lipid Metabolism (original) (raw)
Metabolism| January 09 2015
1Department of Medicine, Columbia University, New York, NY
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1Department of Medicine, Columbia University, New York, NY
2Department of Molecular Metabolic Regulation, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
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1Department of Medicine, Columbia University, New York, NY
3Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA
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1Department of Medicine, Columbia University, New York, NY
4Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Gunma, Japan
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1Department of Medicine, Columbia University, New York, NY
5Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan
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1Department of Medicine, Columbia University, New York, NY
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Diabetes 2015;64(6):1951–1965
Insulin signaling in the liver blunts glucose production and stimulates triglyceride biosynthesis. FoxO1 is required for cAMP induction of hepatic glucose production and is permissive for the effect of insulin to suppress this process. Moreover, FoxO1 ablation increases lipogenesis. In this study, we investigated the pleiotropic actions of FoxO1 on glucose and lipid metabolism. To this end, we reconstituted FoxO1 function in mice with a liver-specific deletion of Foxo1 using targeted knock-in of an allele encoding a DNA binding–deficient FoxO1 mutant (L-DBD). Chow-reared L-DBD mice showed defects in hepatic glucose production but normal liver triglyceride content despite increased rates of de novo lipogenesis and impaired fatty acid oxidation in isolated hepatocytes. Gene expression studies indicated that FoxO1 regulates the expression of glucokinase via a cell-nonautonomous coregulatory mechanism, while its regulation of glucose-6-phosphatase proceeds via a cell-autonomous action as a direct transcriptional activator. These conclusions support a differential regulation of hepatic glucose and lipid metabolism by FoxO1 based on the mechanism by which it alters the expression of key target genes involved in each process.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
2015
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