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Branched-Chain Amino Acid Catabolism in Skeletal Muscle Controls Systemic BCAA Levels Without Impacting Insulin Resistance- [electronic resource]

서명/저자: Branched-Chain Amino Acid Catabolism in Skeletal Muscle Controls Systemic BCAA Levels Without Impacting Insulin Resistance - [electronic resource]

주기사항: Source: Dissertations Abstracts International, Volume: 85-01, Section: B.

초록/해제: 요약Elevated plasma branched-chain amino acids (BCAAs) have been associated with type 2 diabetes since the 1960s. Pharmacological activation of branched-chain α-ketoacid dehydrogenase (BCKDH), the rate-limiting enzyme of BCAA oxidation, lowers plasma BCAAs and improves glucose tolerance in both rodents and humans. However, how BCAA oxidation alleviates insulin resistance, and through which tissues, remains unclear. To address these questions, we developed skeletal muscle and liver-specific BCKDH gain-of-function and loss-of-function mouse models, and comprehensively evaluated glucose homeostasis. We found that altered BCAA oxidation in neither skeletal muscle nor liver, alone or in combination, is sufficient to improve or worsen insulin sensitivity in male mice fed chow or high-fat diet. Modulation of BCKDH activity in skeletal muscle, but not liver, affected fasting plasma BCAAs. However, despite lowering systemic BCAA levels, skeletal muscle-specific increase in BCAA oxidation did not improve insulin sensitivity. These data show that skeletal muscle controls plasma BCAAs, that lowering fasting plasma BCAAs is insufficient to improve insulin sensitivity, and that neither skeletal muscle nor liver account for the improved insulin sensitivity seen with pharmacological activation of BCKDH. Our findings suggest concerted contributions of multiple tissues in the modulation of BCAA metabolism to alter insulin sensitivity.