title: Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways.
abstract: 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.
  
  
  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.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Huang
authors.forename: Houkai
authors.initials: H
authors.lastname: Li
authors.forename: Junjie
authors.initials: J
authors.lastname: Yu
authors.forename: Chunxia
authors.initials: C
authors.lastname: Wang
authors.forename: Shanghai
authors.initials: S
authors.lastname: Chen
authors.forename: Qingshu
authors.initials: Q
authors.lastname: Meng
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheng
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Feifan
authors.initials: F
authors.lastname: Guo
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D007328:Insulin / Q000378:metabolism*; D007930:Leucine / Q000172:deficiency* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; D007930:Leucine