Mitochondrial alpha-keto acid dehydrogenase kinases consisting of pyruvate dehydrogenase kinase isoforms 1-4 (PDKs 1-4) and branched-chain alpha-keto acid dehydrogenase kinase (BDK) are negative metabolic switches that control glucose and branched-chain amino acids (BCAA) oxidation, respectively. These mitochondrial protein kinases deactivate pyruvate dehydrogenase complex (PDC) and the branched-chain alpha-keto acid dehydrogenase complex (BCKDC) by reversible phosphorylation. Recent studies have established the PDK4 and BDK are up-regulated in animal models and patients with obesity and type 2 diabetes (T2D). The inhibition of PDKs and BDK results in enhanced glucose and BCAA oxidation. The results suggest a therapeutic approach to mitigate impaired glucose and BCAA disposal in obesity and T2D. However, to date there have been no potent selective PDK and BDK inhibitors for treatment of these metabolic disorders. The PI's laboratory recently employed structure-based design and high-throughput screening to develop robust highly selective liver-targeting inhibitors for both PDKs and BDK, which were shown to improve glucose tolerance and reduce hepatic steatosis in animal models. In this application, we will test the central hypothesis that mitochondrial PDKs and BDK are novel drug targets for pharmacological approach to obesity and Type 2 diabetes.
Specific Aims are: 1) To provide molecular mechanisms for reduced hepatic steatosis in PDK inhibitor-treated mouse models and to establish liver as a target organ for treatment of obesity and T2D; and 2) To decipher the cause-effect relationship between increased BCAA levels and insulin resistance by enhancing BCKDC flux with BDK inhibitors. The successful outcome of this investigation will provide a framework for developing a new pharmacological approach to the treatment of obesity and T2D.

Public Health Relevance

Obesity has reached epidemic proportions in the United States and is strongly linked to type 2 diabetes. The main objective of this application is to decipher mechanisms for hepatic fat accumulation and insulin resistance associated with these prevalent metabolic disorders. A successful outcome of this research will provide the framework for developing a more effective therapeutic approach to obesity and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK062306-11A1
Application #
8963821
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sechi, Salvatore
Project Start
2002-07-01
Project End
2019-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
11
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Wu, Cheng-Yang; Tso, Shih-Chia; Chuang, Jacinta L et al. (2018) Targeting hepatic pyruvate dehydrogenase kinases restores insulin signaling and mitigates ChREBP-mediated lipogenesis in diet-induced obese mice. Mol Metab 12:12-24
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
Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang et al. (2017) Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors. J Med Chem 60:1142-1150
Perez-Siles, Gonzalo; Ly, Carolyn; Grant, Adrienne et al. (2016) Pathogenic mechanisms underlying X-linked Charcot-Marie-Tooth neuropathy (CMTX6) in patients with a pyruvate dehydrogenase kinase 3 mutation. Neurobiol Dis 94:237-44
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Scheuermann, Thomas H; Brautigam, Chad A (2015) High-precision, automated integration of multiple isothermal titration calorimetric thermograms: new features of NITPIC. Methods 76:87-98
Tso, Shih-Chia; Qi, Xiangbing; Gui, Wen-Jun et al. (2014) Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. J Biol Chem 289:4432-43
Tso, Shih-Chia; Gui, Wen-Jun; Wu, Cheng-Yang et al. (2014) Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain ?-ketoacid dehydrogenase kinase. J Biol Chem 289:20583-93
Kennerson, Marina L; Yiu, Eppie M; Chuang, David T et al. (2013) A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum Mol Genet 22:1404-16

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