In the past funding period, we have identified strong associations between circulating levels of branched- chain amino acids (BCAA-Leu, Val, He) and chronic metabolic diseases in multiple human cohorts. In each case, principal component analysis identified a correlating group of metabolites comprised of all three BCAA, aromatic amino acids (Phe, Tyr), and C3 and C5 acylcarnitines, with disease associations much stronger than for any lipid-related principal component. Feeding studies involving BCAA supplementation of high fat diets demonstrated a contribution of BCAA to development of insulin resistance independent of body weight. However, the increases in BCAA, aromatic amino acids, and related metabolites that we observe in the blood of humans with metabolic diseases is not necessarily driven only by protein consumption, and could also be influenced by rates of amino acid catabolism and protein turnover, or changes in hormones, such as the substantial decrease in IGF-1 levels that we observe in obese humans. Herein, and in close collaboration with the other projects and cores, we will test an evolving model for BCAA-mediated impairment of insulin action involving decreased disposal of BCAA in adipose tissue, and consequent accumulation of BCAA metabolites in skeletal muscle. The role of decreased lGF-1 levels in control of amino acid homeostasis will also be studied. The overarching goal of Project 1 is to fully understand the metabolic and molecular changes that lead to perturbed BCAA homeostasis and loss of insulin sensitivity in animal models, thereby leading to better understanding of possible cause/effect relationships between BCAA and metabolic disease in human subjects.
Specific aims are: 1. To study the time course of changes in pathways of BCAA metabolism during development of insulin resistance in Zucker-obese rats;2. To expand upon our prior studies of dietary supplementation of BCAA in normal rats to include Leu alone and aromatic amino acids;3. To investigate the impact of three maneuvers designed to reverse defects in BCAA metabolism and insulin resistance in Zucker-obese rats;4. To investigate the effects of HF or HF + BCAA feeding on insulin sensitivity, BCAA levels, and BCAA metabolism in mice with reduced circulating IGF-1.

Public Health Relevance

The studies described in this project will contribute to a deeper understanding of the events leading to dysregulated BCAA homeostasis and loss of insulin sensitivity in animal models, thereby leading to better understanding of possible cause/effect relationships between BCAA and metabolic disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK058398-13
Application #
8692743
Study Section
Special Emphasis Panel (ZDK1-GRB-N)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
13
Fiscal Year
2014
Total Cost
$1,347,489
Indirect Cost
$134,657
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2017) Band inversion amplifies 31 P-31 P nuclear overhauser effects: Relaxation mechanism and dynamic behavior of ATP in the human brain by 31 P MRS at 7 T. Magn Reson Med 77:1409-1418
Newgard, Christopher B (2017) Metabolomics and Metabolic Diseases: Where Do We Stand? Cell Metab 25:43-56
Stöckli, Jacqueline; Fisher-Wellman, Kelsey H; Chaudhuri, Rima et al. (2017) Metabolomic analysis of insulin resistance across different mouse strains and diets. J Biol Chem 292:19135-19145
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2016) A simple approach to evaluate the kinetic rate constant for ATP synthesis in resting human skeletal muscle at 7 T. NMR Biomed 29:1240-8
Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49
Kucejova, Blanka; Duarte, Joao; Satapati, Santhosh et al. (2016) Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity. Cell Rep 16:508-519
Zhang, Wenwei; Bu, So Young; Mashek, Mara T et al. (2016) Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins. Cell Rep 15:349-59
Jin, Eunsook S; Sherry, A Dean; Malloy, Craig R (2016) An Oral Load of [13C3]Glycerol and Blood NMR Analysis Detect Fatty Acid Esterification, Pentose Phosphate Pathway, and Glycerol Metabolism through the Tricarboxylic Acid Cycle in Human Liver. J Biol Chem 291:19031-41
Davies, Michael N; Kjalarsdottir, Lilja; Thompson, J Will et al. (2016) The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins. Cell Rep 14:243-54
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2016) Efficient (31) P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T. Magn Reson Med :

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