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.