A Mutant Allele Encoding DNA Binding–Deficient FoxO1 Differentially Regulates Hepatic Glucose and Lipid Metabolism
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, w...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439558/ https://www.ncbi.nlm.nih.gov/pubmed/25576059 http://dx.doi.org/10.2337/db14-1506 |
_version_ | 1782372504358092800 |
---|---|
author | Cook, Joshua R. Matsumoto, Michihiro Banks, Alexander S. Kitamura, Tadahiro Tsuchiya, Kyoichiro Accili, Domenico |
author_facet | Cook, Joshua R. Matsumoto, Michihiro Banks, Alexander S. Kitamura, Tadahiro Tsuchiya, Kyoichiro Accili, Domenico |
author_sort | Cook, Joshua R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4439558 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-44395582016-06-01 A Mutant Allele Encoding DNA Binding–Deficient FoxO1 Differentially Regulates Hepatic Glucose and Lipid Metabolism Cook, Joshua R. Matsumoto, Michihiro Banks, Alexander S. Kitamura, Tadahiro Tsuchiya, Kyoichiro Accili, Domenico Diabetes Metabolism 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. American Diabetes Association 2015-06 2015-01-09 /pmc/articles/PMC4439558/ /pubmed/25576059 http://dx.doi.org/10.2337/db14-1506 Text en © 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. |
spellingShingle | Metabolism Cook, Joshua R. Matsumoto, Michihiro Banks, Alexander S. Kitamura, Tadahiro Tsuchiya, Kyoichiro Accili, Domenico A Mutant Allele Encoding DNA Binding–Deficient FoxO1 Differentially Regulates Hepatic Glucose and Lipid Metabolism |
title | A Mutant Allele Encoding DNA Binding–Deficient FoxO1 Differentially Regulates Hepatic Glucose and Lipid Metabolism |
title_full | A Mutant Allele Encoding DNA Binding–Deficient FoxO1 Differentially Regulates Hepatic Glucose and Lipid Metabolism |
title_fullStr | A Mutant Allele Encoding DNA Binding–Deficient FoxO1 Differentially Regulates Hepatic Glucose and Lipid Metabolism |
title_full_unstemmed | A Mutant Allele Encoding DNA Binding–Deficient FoxO1 Differentially Regulates Hepatic Glucose and Lipid Metabolism |
title_short | A Mutant Allele Encoding DNA Binding–Deficient FoxO1 Differentially Regulates Hepatic Glucose and Lipid Metabolism |
title_sort | mutant allele encoding dna binding–deficient foxo1 differentially regulates hepatic glucose and lipid metabolism |
topic | Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439558/ https://www.ncbi.nlm.nih.gov/pubmed/25576059 http://dx.doi.org/10.2337/db14-1506 |
work_keys_str_mv | AT cookjoshuar amutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT matsumotomichihiro amutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT banksalexanders amutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT kitamuratadahiro amutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT tsuchiyakyoichiro amutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT accilidomenico amutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT cookjoshuar mutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT matsumotomichihiro mutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT banksalexanders mutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT kitamuratadahiro mutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT tsuchiyakyoichiro mutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism AT accilidomenico mutantalleleencodingdnabindingdeficientfoxo1differentiallyregulateshepaticglucoseandlipidmetabolism |