This project investigates the regulation of metabolic flux in the hepatic tricarboxylic acid (TCA cycle) and its role in hepatic insulin resistance. The proposal follows up on key findings in the last funding cycle which indicate that anaplerotic/cataplerotic biosynthetic flux from the TCA cycle and oxidative flux of the TCA cycle are reciprocally regulated and that these pathways are elevated during hepatic insulin resistance. These findings challenge the role of impaired oxidative metabolism as an instigator of hepatic insulin resistance. Thus, we propose a novel hypothesis that elevated hepatic TCA cycle flux is a principal metabolic mediator of pathologies of hepatic insulin resistance by potentiating biosynthetic flux (e.g. gluconeogenesis) and oxidative stress. We test this hypothesis using conditional KO mice, state of the art 13C and 2H tracer based NMR and MS/MS isotopomer methods to evaluate hepatic metabolic fluxes of glucose, lipid and TCA cycle metabolism, and standard evaluation of signaling, gene expression and insulin sensitivity.
The first aim i s to test whether insulin action mediates dys/regulation of TCA cycle fluxes. We determine if acute genetic excision of insulin signaling recapitulates or exasperates elevated TCA cycle flux in HFD mice and whether acute deletion of FOXo1 ameliorates TCA cycle flux and oxidative stress during a HFD. Since these pathways are also subject indirect upregulation by substrate delivery during insulin resistance, the second aim is to determine the mechanism of co-regulation between cataplerotic biosynthesis and oxidative TCA cycle flux. While the acute regulation of these pathways by ATP, NADH and allosteric regulators are known, we will test whether AMPK and Sirt3 act as acute molecular regulators of flux through TCA cycle pathways. Finally, if elevated TCA cycle flux potentiates metabolic pathologies of hepatic insulin resistance, then suppressing TCA cycle pathways should prevent the onset of hepatic complications. Thus, the third aim is to determine if genetic suppression of the cataplerotic or the oxidative span of the TCA cycle results in improved metabolic, oxidative stress and inflammatory response to insulin resistance.
Hepatic insulin resistance contributes to hyperglycemia, hyperlipidemia, fatty liver disease and related inflammatory processes which cause severe liver complications. This proposal addresses a metabolic mechanism that links nearly all complications of hepatic insulin resistance to the central metabolic pathway of the tricarboxylic acid cycle. Completion of this project will conceptually advance our knowledge of insulin resistance and provide a practical advance by identifying a novel therapeutic target against insulin resistance.
|Wu, Cheng-Yang; Satapati, Santhosh; Gui, Wenjun et al. (2018) A novel inhibitor of pyruvate dehydrogenase kinase stimulates myocardial carbohydrate oxidation in diet-induced obesity. J Biol Chem 293:9604-9613|
|Potts, Austin; Uchida, Aki; Deja, Stanislaw et al. (2018) Cytosolic phosphoenolpyruvate carboxykinase as a cataplerotic pathway in the small intestine. Am J Physiol Gastrointest Liver Physiol 315:G249-G258|
|Lan, Tian; Morgan, Donald A; Rahmouni, Kamal et al. (2017) FGF19, FGF21, and an FGFR1/?-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia. Cell Metab 26:709-718.e3|
|Ragavan, Mukundan; Kirpich, Alexander; Fu, Xiaorong et al. (2017) A comprehensive analysis of myocardial substrate preference emphasizes the need for a synchronized fluxomic/metabolomic research design. Am J Physiol Heart Circ Physiol 312:H1215-H1223|
|Silvers, Molly A; Deja, Stanislaw; Singh, Naveen et al. (2017) The NQO1 bioactivatable drug, ?-lapachone, alters the redox state of NQO1+ pancreatic cancer cells, causing perturbation in central carbon metabolism. J Biol Chem 292:18203-18216|
|Kim, Chai-Wan; Addy, Carol; Kusunoki, Jun et al. (2017) Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. Cell Metab 26:394-406.e6|
|Morris, E Matthew; McCoin, Colin S; Allen, Julie A et al. (2017) Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis. J Physiol 595:4909-4926|
|Rauckhorst, Adam J; Gray, Lawrence R; Sheldon, Ryan D et al. (2017) The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity. Mol Metab 6:1468-1479|
|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|
|Satapati, Santhosh; Kucejova, Blanka; Duarte, Joao A G et al. (2016) Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest 126:1605|
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