The branched-chain amino acids (BCAA) accumulated in type 2 diabetes mellitus 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 which increases BCKD activity, was significantly down-regulated in ob/ob and type 2 diabetic mice. Interestingly, in adiponectin knockout (APN-/-) mice fed with 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, 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 up-regulation of PP2Cm expression and BCKD activity were abolished when adenosine monophosphate-activated protein kinase (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.
- Received February 22, 2014.
- Accepted July 9, 2014.
- © 2014 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.