Increased expression of hepatic pyruvate dehydrogenase kinases 2 and 4 in young and middle-aged Otsuka Long-Evans Tokushima Fatty rats: induction by elevated levels of free fatty acids

Bajotto, Gustavo; Murakami, Taro; Nagasaki, Masaru; Qin, Bolin; Matsuo, Yoshiyuki; Maeda, Ken; Ohashi, Masayo; Oshida, Yoshiharu; Sato, Yuzo; Shimomura, Yoshiharu

doi:10.1016/j.metabol.2005.09.014

« Previous Next »Metabolism - Clinical and Experimental
Volume 55, Issue 3 , Pages 317-323, March 2006

Increased expression of hepatic pyruvate dehydrogenase kinases 2 and 4 in young and middle-aged Otsuka Long-Evans Tokushima Fatty rats: induction by elevated levels of free fatty acids

Gustavo Bajotto
- Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya 464-8601, Japan
- Department of Materials Science and Engineering, Nagoya Institute of Technology, Nagoya 466-8555, Japan
Taro Murakami
- Department of Materials Science and Engineering, Nagoya Institute of Technology, Nagoya 466-8555, Japan
Masaru Nagasaki
- Department of Health Science, Aichi Gakuin University, Nisshin 470-0195, Japan
Bolin Qin
- Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya 464-8601, Japan
Yoshiyuki Matsuo
- Department of Materials Science and Engineering, Nagoya Institute of Technology, Nagoya 466-8555, Japan
Ken Maeda
- Department of Materials Science and Engineering, Nagoya Institute of Technology, Nagoya 466-8555, Japan
Masayo Ohashi
- Department of Materials Science and Engineering, Nagoya Institute of Technology, Nagoya 466-8555, Japan
Yoshiharu Oshida
- Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya 464-8601, Japan
Yuzo Sato
- Department of Health Science, Aichi Gakuin University, Nisshin 470-0195, Japan
Yoshiharu Shimomura
- Department of Materials Science and Engineering, Nagoya Institute of Technology, Nagoya 466-8555, Japan
- Corresponding author. Tel.: +81 52 735 5198; fax: +81 52 735 5198.

Received 5 February 2005; accepted 7 September 2005.

Abstract

The activity of the pyruvate dehydrogenase complex (PDC) is regulated by covalent modification of its E1 component, which is catalyzed by specific pyruvate dehydrogenase kinases (PDKs) and phosphatases. In the liver, PDK2 and PDK4 are the most abundant PDK isoforms, which are responsible for inactivation of PDC when glucose availability is scarce in the body. In the present study, regulatory mechanisms of hepatic PDC were examined before and after the onset of type 2 diabetes mellitus in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, using Long-Evans Tokushima Otsuka (LETO) rats as controls. Plasma glucose and insulin concentrations were at normal levels in rats aged 8 weeks, but were significantly higher in OLETF than in LETO rats aged 25 weeks, indicating insulin resistance in OLETF rats. Plasma free fatty acids (FFAs) were 1.6-fold concentrated, and the liver PDC activity was significantly lower in OLETF than in LETO rats at both ages, suggesting suppression of pyruvate oxidative decarboxylation in OLETF rats before and after the onset of diabetes. Pyruvate dehydrogenase kinase activity and abundance of PDK2 and PDK4 proteins, as well as mRNAs, were greater in OLETF rats at both ages. These results suggest that persistently elevated levels of circulating free fatty acid in normal and diabetic OLETF rats play an important role in stimulating PDK2 and PDK4 expression in liver.