Cargando…
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...
Autores principales: | , , , |
---|---|
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 |
_version_ | 1782371099981381632 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4429930 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT titchenellpaulm hepaticinsulinsignalingisdispensableforsuppressionofglucoseoutputbyinsulininvivo AT chuqingwei hepaticinsulinsignalingisdispensableforsuppressionofglucoseoutputbyinsulininvivo AT monksbobbyr hepaticinsulinsignalingisdispensableforsuppressionofglucoseoutputbyinsulininvivo AT birnbaummorrisj hepaticinsulinsignalingisdispensableforsuppressionofglucoseoutputbyinsulininvivo |