Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism
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Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism. / Macotela, Yazmin; Emanuelli, Brice; Bång, Anneli M; Espinoza, Daniel O; Boucher, Jeremie; Beebe, Kirk; Gall, Walter; Kahn, C Ronald.
In: PLOS ONE, Vol. 6, No. 6, 2011, p. e21187.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 6
SP - e21187
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 6
ER -
ID: 143328483