Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism

TY - JOUR

T1 - Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism

AU - Macotela, Yazmin

AU - Emanuelli, Brice

AU - Bång, Anneli M

AU - Espinoza, Daniel O

AU - Boucher, Jeremie

AU - Beebe, Kirk

AU - Gall, Walter

AU - Kahn, C Ronald

PY - 2011

Y1 - 2011

N2 - Environmental factors, such as the macronutrient composition of the diet, can have a profound impact on risk of diabetes and metabolic syndrome. In the present study we demonstrate how a single, simple dietary factor--leucine--can modify insulin resistance by acting on multiple tissues and at multiple levels of metabolism. Mice were placed on a normal or high fat diet (HFD). Dietary leucine was doubled by addition to the drinking water. mRNA, protein and complete metabolomic profiles were assessed in the major insulin sensitive tissues and serum, and correlated with changes in glucose homeostasis and insulin signaling. After 8 weeks on HFD, mice developed obesity, fatty liver, inflammatory changes in adipose tissue and insulin resistance at the level of IRS-1 phosphorylation, as well as alterations in metabolomic profile of amino acid metabolites, TCA cycle intermediates, glucose and cholesterol metabolites, and fatty acids in liver, muscle, fat and serum. Doubling dietary leucine reversed many of the metabolite abnormalities and caused a marked improvement in glucose tolerance and insulin signaling without altering food intake or weight gain. Increased dietary leucine was also associated with a decrease in hepatic steatosis and a decrease in inflammation in adipose tissue. These changes occurred despite an increase in insulin-stimulated phosphorylation of p70S6 kinase indicating enhanced activation of mTOR, a phenomenon normally associated with insulin resistance. These data indicate that modest changes in a single environmental/nutrient factor can modify multiple metabolic and signaling pathways and modify HFD induced metabolic syndrome by acting at a systemic level on multiple tissues. These data also suggest that increasing dietary leucine may provide an adjunct in the management of obesity-related insulin resistance.

AB - Environmental factors, such as the macronutrient composition of the diet, can have a profound impact on risk of diabetes and metabolic syndrome. In the present study we demonstrate how a single, simple dietary factor--leucine--can modify insulin resistance by acting on multiple tissues and at multiple levels of metabolism. Mice were placed on a normal or high fat diet (HFD). Dietary leucine was doubled by addition to the drinking water. mRNA, protein and complete metabolomic profiles were assessed in the major insulin sensitive tissues and serum, and correlated with changes in glucose homeostasis and insulin signaling. After 8 weeks on HFD, mice developed obesity, fatty liver, inflammatory changes in adipose tissue and insulin resistance at the level of IRS-1 phosphorylation, as well as alterations in metabolomic profile of amino acid metabolites, TCA cycle intermediates, glucose and cholesterol metabolites, and fatty acids in liver, muscle, fat and serum. Doubling dietary leucine reversed many of the metabolite abnormalities and caused a marked improvement in glucose tolerance and insulin signaling without altering food intake or weight gain. Increased dietary leucine was also associated with a decrease in hepatic steatosis and a decrease in inflammation in adipose tissue. These changes occurred despite an increase in insulin-stimulated phosphorylation of p70S6 kinase indicating enhanced activation of mTOR, a phenomenon normally associated with insulin resistance. These data indicate that modest changes in a single environmental/nutrient factor can modify multiple metabolic and signaling pathways and modify HFD induced metabolic syndrome by acting at a systemic level on multiple tissues. These data also suggest that increasing dietary leucine may provide an adjunct in the management of obesity-related insulin resistance.

KW - Adenylate Kinase

KW - Adipose Tissue

KW - Adiposity

KW - Animals

KW - Body Weight

KW - Diet

KW - Dietary Fats

KW - Dietary Supplements

KW - Fatty Liver

KW - Feeding Behavior

KW - Glucose Tolerance Test

KW - Inflammation

KW - Insulin

KW - Insulin Resistance

KW - Leucine

KW - Liver

KW - Metabolomics

KW - Mice

KW - Muscles

KW - Ribosomal Protein S6 Kinases, 70-kDa

KW - Signal Transduction

U2 - 10.1371/journal.pone.0021187

DO - 10.1371/journal.pone.0021187

M3 - Journal article

C2 - 21731668

SN - 1932-6203

VL - 6

SP - e21187

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 6

ER -