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Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways

OBJECTIVE: We have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellul...

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Autores principales: Xiao, Fei, Huang, Zhiying, Li, Houkai, Yu, Junjie, Wang, Chunxia, Chen, Shanghai, Meng, Qingshu, Cheng, Ying, Gao, Xiang, Li, Jia, Liu, Yong, Guo, Feifan
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046835/
https://www.ncbi.nlm.nih.gov/pubmed/21282364
http://dx.doi.org/10.2337/db10-1246
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author Xiao, Fei
Huang, Zhiying
Li, Houkai
Yu, Junjie
Wang, Chunxia
Chen, Shanghai
Meng, Qingshu
Cheng, Ying
Gao, Xiang
Li, Jia
Liu, Yong
Guo, Feifan
author_facet Xiao, Fei
Huang, Zhiying
Li, Houkai
Yu, Junjie
Wang, Chunxia
Chen, Shanghai
Meng, Qingshu
Cheng, Ying
Gao, Xiang
Li, Jia
Liu, Yong
Guo, Feifan
author_sort Xiao, Fei
collection PubMed
description OBJECTIVE: We have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms. RESEARCH DESIGN AND METHODS: Changes in metabolic parameters and expression of genes and proteins involved in regulation of insulin sensitivity were analyzed in mice, human HepG2 cells, and mouse primary hepatocytes under leucine deprivation. RESULTS: We show that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control nonderepressible (GCN)2 and decreasing mammalian target of rapamycin/S6K1 signaling. In addition, we show that activation of AMP-activated protein kinase also contributes to leucine deprivation–increased hepatic insulin sensitivity. Finally, we show that leucine deprivation improves insulin sensitivity under insulin-resistant conditions. CONCLUSIONS: This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation. Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity. These observations provide a rationale for short-term dietary restriction of leucine for the treatment of insulin resistance and associated metabolic diseases.
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spelling pubmed-30468352012-03-01 Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways Xiao, Fei Huang, Zhiying Li, Houkai Yu, Junjie Wang, Chunxia Chen, Shanghai Meng, Qingshu Cheng, Ying Gao, Xiang Li, Jia Liu, Yong Guo, Feifan Diabetes Metabolism OBJECTIVE: We have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms. RESEARCH DESIGN AND METHODS: Changes in metabolic parameters and expression of genes and proteins involved in regulation of insulin sensitivity were analyzed in mice, human HepG2 cells, and mouse primary hepatocytes under leucine deprivation. RESULTS: We show that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control nonderepressible (GCN)2 and decreasing mammalian target of rapamycin/S6K1 signaling. In addition, we show that activation of AMP-activated protein kinase also contributes to leucine deprivation–increased hepatic insulin sensitivity. Finally, we show that leucine deprivation improves insulin sensitivity under insulin-resistant conditions. CONCLUSIONS: This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation. Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity. These observations provide a rationale for short-term dietary restriction of leucine for the treatment of insulin resistance and associated metabolic diseases. American Diabetes Association 2011-03 2011-02-21 /pmc/articles/PMC3046835/ /pubmed/21282364 http://dx.doi.org/10.2337/db10-1246 Text en © 2011 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. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Metabolism
Xiao, Fei
Huang, Zhiying
Li, Houkai
Yu, Junjie
Wang, Chunxia
Chen, Shanghai
Meng, Qingshu
Cheng, Ying
Gao, Xiang
Li, Jia
Liu, Yong
Guo, Feifan
Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways
title Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways
title_full Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways
title_fullStr Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways
title_full_unstemmed Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways
title_short Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways
title_sort leucine deprivation increases hepatic insulin sensitivity via gcn2/mtor/s6k1 and ampk pathways
topic Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046835/
https://www.ncbi.nlm.nih.gov/pubmed/21282364
http://dx.doi.org/10.2337/db10-1246
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