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Diabetes. 2015 Jan;64(1):49-59. doi: 10.2337/db14-0312. Epub 2014 Jul 28.

Impaired adiponectin signaling contributes to disturbed catabolism of branched-chain amino acids in diabetic mice.

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  • 1Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 2Experiment Teaching Center, Fourth Military Medical University, Xi'an, China.
  • 3Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China Department of Cardiology, 306th Hospital of PLA, Beijing, China.
  • 4Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 5Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China lingtao2006@gmail.com.

Abstract

The branched-chain amino acids (BCAA) accumulated in type 2 diabetes are independent contributors to insulin resistance. The activity of branched-chain α-keto acid dehydrogenase (BCKD) complex, rate-limiting enzyme in BCAA catabolism, is reduced in diabetic states, which contributes to elevated BCAA concentrations. However, the mechanisms underlying decreased BCKD activity remain poorly understood. Here, we demonstrate that mitochondrial phosphatase 2C (PP2Cm), a newly identified BCKD phosphatase that increases BCKD activity, was significantly downregulated in ob/ob and type 2 diabetic mice. Interestingly, in adiponectin (APN) knockout (APN(-/-)) mice fed with a high-fat diet (HD), PP2Cm expression and BCKD activity were significantly decreased, whereas BCKD kinase (BDK), which inhibits BCKD activity, was markedly increased. Concurrently, plasma BCAA and branched-chain α-keto acids (BCKA) were significantly elevated. APN treatment markedly reverted PP2Cm, BDK, BCKD activity, and BCAA and BCKA levels in HD-fed APN(-/-) and diabetic animals. Additionally, increased BCKD activity caused by APN administration was partially but significantly inhibited in PP2Cm knockout mice. Finally, APN-mediated upregulation of PP2Cm expression and BCKD activity were abolished when AMPK was inhibited. Collectively, we have provided the first direct evidence that APN is a novel regulator of PP2Cm and systematic BCAA levels, suggesting that targeting APN may be a pharmacological approach to ameliorating BCAA catabolism in the diabetic state.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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