Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice

Metabolism. 2014 Jun;63(6):841-50. doi: 10.1016/j.metabol.2014.03.006. Epub 2014 Mar 15.


Objective: We recently discovered that leucine deprivation increases hepatic insulin sensitivity via general control nondepressible (GCN) 2/mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways. The goal of the present study was to investigate whether the above effects were leucine specific or were also induced by deficiency of other branched chain amino acids including valine and isoleucine.

Methods: Following depletion of BCAAs, changes in metabolic parameters and the expression of genes and proteins involved in regulation of insulin sensitivity and glucose metabolism were analyzed in mice and cell lines including human HepG2 cells, primary mouse hepatocytes and a mouse myoblast cell line C2C12.

Results: Valine or isoleucine deprivation for 7 days has similar effect on improving insulin sensitivity as leucine, in wild type and insulin-resistant mice models. These effects are possibly mediated by decreased mTOR/S6K1 and increased AMPK signaling pathways, in a GCN2-dependent manner. Similar observations were obtained in in vitro studies. In contrast to leucine withdrawal, valine or isoleucine deprivation for 7 days significantly decreased fed blood glucose levels, possibly due to reduced expression of a key gluconeogenesis gene, glucose-6-phosphatase. Finally, insulin sensitivity was rapidly improved in mice 1 day following maintenance on a diet deficient for any individual BCAAs.

Conclusions: Our results show that while improvement on insulin sensitivity is a general feature of BCAAs depletion, individual BCAAs have specific effects on metabolic pathways, including those that regulate glucose level. These observations provide a conceptual framework for delineating the molecular mechanisms that underlie amino acid regulation of insulin sensitivity.

Keywords: Glucose metabolism; Insulin signaling; Isoleucine deprivation; Leucine deprivation; Valine deprivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Amino Acids, Branched-Chain / metabolism
  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • Blotting, Western
  • Cell Line
  • Gluconeogenesis / genetics
  • Glucose-6-Phosphatase / genetics
  • Glucose-6-Phosphatase / metabolism
  • Hep G2 Cells
  • Hepatocytes / metabolism*
  • Humans
  • Insulin Resistance*
  • Isoleucine / deficiency
  • Isoleucine / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Valine / deficiency
  • Valine / metabolism*


  • Amino Acids, Branched-Chain
  • Blood Glucose
  • Isoleucine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • AMP-Activated Protein Kinases
  • Glucose-6-Phosphatase
  • Valine