Regulation of hepatic branched-chain α-ketoacid dehydrogenase complex in rats fed a high-fat diet.

Branched-chain α-ketoacid (BCKA) dehydrogenase complex (BCKDC) regulates branched-chain amino acid (BCAA) metabolism at the level of BCKA catabolism. It has been demonstrated that the activity of hepatic BCKDC is markedly decreased in type 2 diabetic animal models. In this study, we examined the regulation of hepatic BCKDC in rats with diet-induced obesity (DIO). Rats were fed a control or a 60% of energy high-fat diet (HFD) for twelve weeks. Concentrations of blood components and the activities and protein amounts of hepatic BCKDC and its specific kinase (BDK) were measured. The concentrations of plasma glucose, insulin, and corticosterone were significantly elevated in DIO rats compared to those fed the control diet, suggestive of insulin resistance. Blood BCAA concentrations were not increased. The activity of hepatic BCKDC that was present in the active form in the liver was higher in DIO rats compared to controls, although the total activity and the enzyme amount were not different between two diet groups. The activity of hepatic BDK and the abundance of BDK bound to the BCKDC were decreased in DIO rats. The total amount of hepatic BDK was also significantly decreased in DIO rats. In rats made obese through HFD feeding, in contrast to prior studies in rat models of type 2 diabetes, hepatic BDK was down-regulated and thereby hepatic BCKDC was activated, suggesting that DIO promotes liver BCKA catabolism. In this model there was no evidence that increased blood BCAAs drive DIO-associated insulin resistance, since concentrations of BCAAs were not altered by DIO.