title: Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism.
abstract: 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.
authors: Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Yazmin
authors: Y
authors: Macotela
authors: Brice
authors: B
authors: Emanuelli
authors: Anneli M
authors: AM
authors: Bång
authors: Daniel O
authors: DO
authors: Espinoza
authors: Jeremie
authors: J
authors: Boucher
authors: Kirk
authors: K
authors: Beebe
authors: Walter
authors: W
authors: Gall
authors: C Ronald
authors: CR
authors: Kahn
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D019587:Dietary Supplements; D005234:Fatty Liver / Q000188:drug therapy; D005247:Feeding Behavior / Q000187:drug effects; D005951:Glucose Tolerance Test; D007249:Inflammation / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007930:Leucine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D055432:Metabolomics; D051379:Mice; D009132:Muscles / Q000187:drug effects / Q000201:enzymology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004041:Dietary Fats; D007328:Insulin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000263:Adenylate Kinase; D007930:Leucine