title: Impaired adiponectin signaling contributes to disturbed catabolism of branched-chain amino acids in diabetic mice.
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.
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Kun
authors: K
authors: Lian
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Chaosheng
authors: C
authors: Du
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Yi
authors: Y
authors: Liu
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Di
authors: D
authors: Zhu
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Wenjun
authors: W
authors: Yan
authors: Experiment Teaching Center, Fourth Military Medical University, Xi'an, China.
authors: Haifeng
authors: H
authors: Zhang
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Zhibo
authors: Z
authors: Hong
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China Department of Cardiology, 306th Hospital of PLA, Beijing, China.
authors: Peilin
authors: P
authors: Liu
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Lijian
authors: L
authors: Zhang
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Haifeng
authors: H
authors: Pei
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Jinglong
authors: J
authors: Zhang
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Chao
authors: C
authors: Gao
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Chao
authors: C
authors: Xin
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Hexiang
authors: H
authors: Cheng
authors: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Lize
authors: L
authors: Xiong
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China lingtao2006@gmail.com.
authors: Ling
authors: L
authors: Tao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics* / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D008375:Maple Syrup Urine Disease / Q000235:genetics / Q000378:metabolism; D008660:Metabolism / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D000597:Amino Acids, Branched-Chain; D034741:RNA, Small Interfering; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C