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United States Department of Agriculture

Agricultural Research Service

Research Project: Linking Foods, Behavior and Metabolism to Promote a Healthy Body Weight

Location: Obesity and Metabolism Research Unit

Title: Regulation of hepatic branched-chain alpha-keto acid dehydrogenase complex in rats fed a high-fat diet

Authors
item Kadota, Yohihiro -
item Toyoda, Takanari -
item Kitaura, Yasuyuki -
item Adams, Sean
item Shimomura, Yoshiharu -

Submitted to: Obesity Research & Clinical Practice
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 24, 2013
Publication Date: December 1, 2013
Citation: Kadota, Y., Toyoda, T., Kitaura, Y., Adams, S.H., Shimomura, Y. 2013. Regulation of hepatic branched-chain alpha-keto acid dehydrogenase complex in rats fed a high-fat diet. Obesity Research & Clinical Practice. 7:e439-e444. DOI: 10.101016/j.orcp.2013.07.003.

Interpretive Summary: Branched-chain alpha-keto acid dehydrogenase complex (BCKDC) regulates the utilization of important essential amino acids, the branched-chain amino acids (BCAAs) at the level of branched chain alpha-ketoacid (BCKA) catabolism. It has been demonstrated that the activity of liver BCKDC is markedly decreased in type 2 diabetic animal models, suggesting that under diabetic conditions combustion of BCAAs to energy in the liver is compromised. Obesity is characterized by poor metabolic health, even in the absence of overt diabetes, yet little is known about how the liver handles amino acids obese conditinos. Thus, we examined the regulation of hepatic BCKDC in rats eating a high fat diet to induce obesity and high blood levels of the hormone insulin (hyperinsulinemia). Rats were fed a control diet or a 60% of energy high-fat diet (n=7 each) for twelve weeks. Concentrations of blood components and the activities and protein amounts of hepatic BCKDC and its specific regulatory kinase (BDK) were measured. Results: The concentrations of blood sugar, insulin, and corticosterone were significantly elevated in DIO rats compared to those fed the control diet. The activity of the 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 liver BDK and the abundance of BDK bound to the BCKDC were decreased in rats fed the high-fat diet. The total amount of hepatic BDK was also significantly decreased in rats fed the high-fat diet. Conclusion: In rats made obese through high-fat diet 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 BCAA catabolism. If true in the human condition, then the liver's handling of certain amino acids in the pre-diabetic, obese state may be maintained or even activated, unlike in diabetes in which BCAA utilization may be lower and thus impact protein metabolism adversely. Importantly, this study indicates that resistance to the blood sugar regulating hormone insulin ("insulin resistance") that occurs with obesity is not triggered by changes in BCAA, since the latter remained stable in the obese animal model used herein.

Technical Abstract: Objective: Branched-chain alpha-keto acid dehydrogenase complex (BCKDC) regulates branched-chain amino acid (BCAA) metabolism at the level of branched chain alpha-ketoacid (BCKA) catabolism. It has been demonstrated that the activity of hepatic BCKDC is markedly decreased in type 2 diabetic animal models. In the present study, we examined the regulation of the hepatic BCKDC in rats with diet-induced obesity (DIO). Methods: Rats were fed a control diet or a 60% of energy high-fat diet (n=7 each) for twelve weeks. Concentrations of blood components and the activities and protein amounts of hepatic BCKDC and its specific kinase (BDK) were measured. Results: The concentrations of plasma glucose, insulin, and corticosterone were significantly elevated in DIO rats compared to those fed the control diet. The activity of the 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 rats fed the high-fat diet. The total amount of hepatic BDK was also significantly decreased in rats fed the high-fat diet. Conclusion: In rats made obese through high-fat diet 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 BCAA (BCKA) catabolism. In this model there was no evidence that increased blood BCAA drive DIO-associated insulin resistance, since concentrations of BCAA were not altered by DIO.

Last Modified: 8/22/2014
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