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.
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.
|Shantavasinkul, Prapimporn Chattranukulchai; Muehlbauer, Michael J; Bain, James R et al. (2018) Improvement in insulin resistance after gastric bypass surgery is correlated with a decline in plasma 2-hydroxybutyric acid. Surg Obes Relat Dis 14:1126-1132|
|McGarrah, Robert W; Crown, Scott B; Zhang, Guo-Fang et al. (2018) Cardiovascular Metabolomics. Circ Res 122:1238-1258|
|Fisher-Wellman, Kelsey H; Davidson, Michael T; Narowski, Tara M et al. (2018) Mitochondrial Diagnostics: A Multiplexed Assay Platform for Comprehensive Assessment of Mitochondrial Energy Fluxes. Cell Rep 24:3593-3606.e10|
|Jin, Eunsook S; Lee, Min Hee; Murphy, Rebecca E et al. (2018) Pentose phosphate pathway activity parallels lipogenesis but not antioxidant processes in rat liver. Am J Physiol Endocrinol Metab 314:E543-E551|
|Ren, Jimin; Shang, Ty; Sherry, A Dean et al. (2018) Unveiling a hidden 31 P signal coresonating with extracellular inorganic phosphate by outer-volume-suppression and localized 31 P MRS in the human brain at 7T. Magn Reson Med 80:1289-1297|
|An, Jie; Wang, Liping; Patnode, Michael L et al. (2018) Physiological mechanisms of sustained fumagillin-induced weight loss. JCI Insight 3:|
|Peterson, Brett S; Campbell, Jonathan E; Ilkayeva, Olga et al. (2018) Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or ? Cell Metabolism in the Absence of Overnutrition. Cell Rep 24:209-223.e6|
|White, Phillip J; McGarrah, Robert W; Grimsrud, Paul A et al. (2018) The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase. Cell Metab 27:1281-1293.e7|
|Jin, Eunsook S; Browning, Jeffrey D; Murphy, Rebecca E et al. (2018) Fatty liver disrupts glycerol metabolism in gluconeogenic and lipogenic pathways in humans. J Lipid Res 59:1685-1694|
|Newgard, Christopher B (2017) Metabolomics and Metabolic Diseases: Where Do We Stand? Cell Metab 25:43-56|
Showing the most recent 10 out of 181 publications