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

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 3; pp. 746 - 756
• Main Authors: Xiao, Fei, Huang, Zhiying, Li, Houkai, Yu, Junjie, Wang, Chunxia, Chen, Shanghai, Meng, Qingshu, Cheng, Ying, Gao, Xiang, Li, Jia, Liu, Yong, Guo, Feifan
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-03-2011
• Subjects: Adenoviruses; Adenylate Kinase - metabolism; Adipose Tissue - metabolism; Amino acids; Animals; Biological and medical sciences; Blood Glucose - metabolism; Blotting, Western; Cells, Cultured; Cellular signal transduction; Development and progression; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genetic aspects; Glucose; Homeostasis; Insulin - metabolism; Insulin resistance; Kinases; Laboratory animals; Leucine; Leucine - deficiency; Leucine - metabolism; Liver - metabolism; Male; Medical sciences; Metabolic disorders; Metabolism; Mice; Muscle, Skeletal - metabolism; Physiological aspects; Plasmids; Protein-Serine-Threonine Kinases - metabolism; Proteins; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Risk factors; Signal Transduction - physiology; TOR Serine-Threonine Kinases - metabolism; China; Endocrinopathy; Pancreatic hormone; Sensitivity; Aminoacid; Diabetes mellitus; Leucine; Insulin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db10-1246

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.
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.
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.
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.