This project seeks to understand the metabolic origins of skeletal muscle insulin resistance, a physiological abnormality common to obesity, diabetes and aging. In recent studies that applied targeted metabolomics we discovered that the early stages of diet-induced weight gain and glucose intolerance are accompanied by increased fat oxidation and intramuscular accumulation of mitochondrial-derived acylcarnitine metabolites, byproducts of incomplete substrate catabolism. Likewise, the addition of branched chain amino acids (BCAA) to a high fat diet exacerbated insulin resistance while provoking a further increase in muscle levels of both lipid- and amino acid-derived acylcarnitines. These metabolomic signatures suggest that the mechanisms underlying diet-induced insulin resistance might be directly related to carbon load within the mitochondrial compartment. Thus, the overarching goal of this project is to test the hypothesis that excessive mitochondrial lipid and BCAA catabolism plays a central role in triggering mitochondrial stress, insulin resistance and eventual metabolic failure during the pathological progression of diet-induced obesity. Our working model predicts that acylcarnitines accumulation in the obese state reflects a mitochondrial environment that is conducive to hyperacetylation of mitochondrial proteins and increased generation of reactive oxygen species. These hypotheses will be tested by combining state-of-the-art metabolomics and metabolic flux analyses with genetically modified mouse models harboring targeted manipulations in fat oxidation and acylcarnitines production. This project is germane to current antiobesity and antidiabetic drug development efforts aimed at increasing skeletal muscle fat oxidation, and could lead to paradigm shifting insights into the interplay between mitochondrial function and insulin action in muscle.

Public Health Relevance

Weight gain, caloric surplus and physical inactivity disrupt glucose disposal into skeletal muscle, which in turn increases risk of cardiometabolic diseases such as type 2 diabetes. By examining obesity-related perturbations in mitochondrial fatty acid and amino acid metabolism, this project will aid efforts to understand, treat and prevent insulin resistance and glucose intolerance.

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 #
8692744
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
$376,800
Indirect Cost
$136,800
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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