The hypothesis that PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) has potential as a target for the treatment of type 2 diabetes was tested by feeding wild-type and PDHK4 knockout mice a high saturated fat diet that induces hyperglycemia, hyperinsulinaemia, glucose intolerance, hepatic steatosis and obesity. Previous studies have shown that PDHK4 deficiency lowers blood glucose by limiting the supply of three carbon gluconeogenic substrates to the liver. There is concern, however, that the increase in glucose oxidation caused by less inhibition of the pyruvate dehydrogenase complex by phosphorylation will inhibit fatty acid oxidation, promote ectopic fat accumulation and worsen insulin sensitivity. This was examined by feeding wild-type and PDHK4 knockout mice a high saturated fat diet for 8 months. Fasting blood glucose levels increased gradually in both groups but remained significantly lower in the PDHK4 knockout mice. Hyperinsulinaemia developed in both groups, but glucose tolerance was better and body weight was lower in the PDHK4 knockout mice. At termination, less fat was present in the liver and skeletal muscle of the PDHK4 knockout mice. Higher amounts of PGC-1α [PPARγ (peroxisome proliferator-activated receptor γ) coactivator 1α] and PPARα and lower amounts of fatty acid synthase and acetyl-CoA carboxylase isoenzyme 1 were present in the liver of the PDHK4 knockout mice. These findings suggest PDHK4 deficiency creates conditions that alter upstream signalling components involved in the regulation of lipid metabolism. The findings support the hypothesis that PDHK4 is a viable target for the treatment of type 2 diabetes.
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Research Article|
September 25 2009
Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency attenuates the long-term negative effects of a high-saturated fat diet
Byounghoon Hwang;
Byounghoon Hwang
1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A. and Richard Roudebush Veterans Affairs Medical Center, 1481 West Tenth Street, Indianapolis, IN 46202, U.S.A.
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Nam Ho Jeoung;
Nam Ho Jeoung
1
1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A. and Richard Roudebush Veterans Affairs Medical Center, 1481 West Tenth Street, Indianapolis, IN 46202, U.S.A.
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Robert A. Harris
Robert A. Harris
2
1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A. and Richard Roudebush Veterans Affairs Medical Center, 1481 West Tenth Street, Indianapolis, IN 46202, U.S.A.
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
March 09 2009
Revision Received:
July 16 2009
Accepted:
July 23 2009
Accepted Manuscript online:
July 23 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 423 (2): 243–252.
Article history
Received:
March 09 2009
Revision Received:
July 16 2009
Accepted:
July 23 2009
Accepted Manuscript online:
July 23 2009
Citation
Byounghoon Hwang, Nam Ho Jeoung, Robert A. Harris; Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency attenuates the long-term negative effects of a high-saturated fat diet. Biochem J 15 October 2009; 423 (2): 243–252. doi: https://doi.org/10.1042/BJ20090390
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