Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.
Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.
Shin, AC; Fasshauer, M; Filatova, N; Grundell, LA; Zielinski, E; Zhou, J-Y; Scherer, T; Lindtner, C; White, PJ; Lapworth, AL; Ilkayeva, O; Knippschild, U; Wolf, AM; Scheja, L; Grove, KL; Smith, RD; Qian, W-J; Lynch, CJ; Newgard, CB; Buettner, C
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