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Impaired Adiponectin Signaling Contributes to Disturbed Catabolism of Branched-Chain Amino Acids in Diabetic Mice
- Source :
- Diabetes. 64:49-59
- Publication Year :
- 2014
- Publisher :
- American Diabetes Association, 2014.
-
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.
- Subjects :
- Male
medicine.medical_specialty
animal structures
Endocrinology, Diabetes and Metabolism
Phosphatase
Mice, Obese
AMP-Activated Protein Kinases
Biology
Pyruvate dehydrogenase phosphatase
Diet, High-Fat
Diabetes Mellitus, Experimental
Insulin resistance
Maple Syrup Urine Disease
AMP-activated protein kinase
Internal medicine
Phosphoprotein Phosphatases
Internal Medicine
medicine
Animals
RNA, Small Interfering
Cells, Cultured
Mice, Knockout
Adiponectin
Catabolism
AMPK
medicine.disease
Mice, Inbred C57BL
Protein Phosphatase 2C
Metabolism
Endocrinology
Diabetes Mellitus, Type 2
Knockout mouse
Hepatocytes
biology.protein
Amino Acids, Branched-Chain
hormones, hormone substitutes, and hormone antagonists
Signal Transduction
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 64
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....c9721f077ea9cf60e3b291201c116b8a
- Full Text :
- https://doi.org/10.2337/db14-0312