Gender difference in regulation of branched-chain amino acid catabolism

Abstract

Regulation of the activity state of the hepatic branched-chain 2-oxo acid dehydrogenase (BCODH) complex during the light-dark cycle differs markedly in male and female rats. Female rats exhibit a profound diurnal rhythm in the activity state of the complex that is not observed in male rats. Regardless of gender, most of the complex was dephosphorylated and active in the middle of the dark period and early in the light period, and this form of the complex predominated in male rats at the end of the light period. In contrast, most of the complex in female rats became phosphorylated and inactive by the end of the light period. Gonadectomy prevented the diurnal rhythm in females but was without effect in males, indicating that female sex hormones are required for this gender difference in regulation of the BCODH complex. Changes in levels of branched-chain 2-oxo acids, known regulators of BCODH kinase, do not seem to be involved; rather, an increase in BCODH kinase activity occurring between morning and evening is responsible for inactivation of the BCODH complex in female rats. The increase in kinase activity is due to an increase in the amount of kinase protein associated with the BCODH complex. Thus a marked diurnal variation in the amount of BCODH kinase and therefore its activity results in large swings in the activity state of the liver BCODH complex in female rats. This study provides the first evidence for a gender-specific difference in the regulation of branched-chain amino acid catabolism.