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Hepatic Insulin Signaling is Dispensable for Suppression of Glucose Output by Insulin in Vivo

Insulin signaling and nutrient levels coordinate the metabolic response to feeding in the liver. Insulin signals in hepatocytes to activate Akt, which inhibits Foxo1 suppressing hepatic glucose production (HGP) and allowing the transition to the postprandial state. Here we provide genetic evidence t...

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Autores principales: Titchenell, Paul M., Chu, Qingwei, Monks, Bobby R., Birnbaum, Morris J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429930/
https://www.ncbi.nlm.nih.gov/pubmed/25963408
http://dx.doi.org/10.1038/ncomms8078
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author Titchenell, Paul M.
Chu, Qingwei
Monks, Bobby R.
Birnbaum, Morris J.
author_facet Titchenell, Paul M.
Chu, Qingwei
Monks, Bobby R.
Birnbaum, Morris J.
author_sort Titchenell, Paul M.
collection PubMed
description Insulin signaling and nutrient levels coordinate the metabolic response to feeding in the liver. Insulin signals in hepatocytes to activate Akt, which inhibits Foxo1 suppressing hepatic glucose production (HGP) and allowing the transition to the postprandial state. Here we provide genetic evidence that insulin regulates HGP by both direct and indirect hepatic mechanisms. Liver-specific ablation of the IR (L-Insulin Receptor KO) induces glucose intolerance, insulin resistance and prevents the appropriate transcriptional response to feeding. Liver-specific deletion of Foxo1 (L-IRFoxo1DKO) rescues glucose tolerance and allows for normal suppression of HGP and gluconeogenic gene expression in response to insulin despite lack of autonomous liver insulin signaling. These data indicate that, in the absence of Foxo1, insulin signals via an intermediary extra-hepatic tissue to regulate liver glucose production. Importantly, a hepatic mechanism distinct from the IR-Akt-Foxo1 axis exists to regulate glucose production.
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spelling pubmed-44299302015-11-12 Hepatic Insulin Signaling is Dispensable for Suppression of Glucose Output by Insulin in Vivo Titchenell, Paul M. Chu, Qingwei Monks, Bobby R. Birnbaum, Morris J. Nat Commun Article Insulin signaling and nutrient levels coordinate the metabolic response to feeding in the liver. Insulin signals in hepatocytes to activate Akt, which inhibits Foxo1 suppressing hepatic glucose production (HGP) and allowing the transition to the postprandial state. Here we provide genetic evidence that insulin regulates HGP by both direct and indirect hepatic mechanisms. Liver-specific ablation of the IR (L-Insulin Receptor KO) induces glucose intolerance, insulin resistance and prevents the appropriate transcriptional response to feeding. Liver-specific deletion of Foxo1 (L-IRFoxo1DKO) rescues glucose tolerance and allows for normal suppression of HGP and gluconeogenic gene expression in response to insulin despite lack of autonomous liver insulin signaling. These data indicate that, in the absence of Foxo1, insulin signals via an intermediary extra-hepatic tissue to regulate liver glucose production. Importantly, a hepatic mechanism distinct from the IR-Akt-Foxo1 axis exists to regulate glucose production. 2015-05-12 /pmc/articles/PMC4429930/ /pubmed/25963408 http://dx.doi.org/10.1038/ncomms8078 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Titchenell, Paul M.
Chu, Qingwei
Monks, Bobby R.
Birnbaum, Morris J.
Hepatic Insulin Signaling is Dispensable for Suppression of Glucose Output by Insulin in Vivo
title Hepatic Insulin Signaling is Dispensable for Suppression of Glucose Output by Insulin in Vivo
title_full Hepatic Insulin Signaling is Dispensable for Suppression of Glucose Output by Insulin in Vivo
title_fullStr Hepatic Insulin Signaling is Dispensable for Suppression of Glucose Output by Insulin in Vivo
title_full_unstemmed Hepatic Insulin Signaling is Dispensable for Suppression of Glucose Output by Insulin in Vivo
title_short Hepatic Insulin Signaling is Dispensable for Suppression of Glucose Output by Insulin in Vivo
title_sort hepatic insulin signaling is dispensable for suppression of glucose output by insulin in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429930/
https://www.ncbi.nlm.nih.gov/pubmed/25963408
http://dx.doi.org/10.1038/ncomms8078
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