Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism

作者：Shin Andrew C; Fasshauer Martin; Filatova Nika; Grundell Linus A; Zielinski Elizabeth; Zhou Jian Ying; Scherer Thomas; Lindtner Claudia; White Phillip J; Lapworth Amanda L; Ilkayeva Olga; Knippschild Uwe; Wolf Anna M; Scheja Ludger; Grove Kevin L; Smith Richard D; Qian Wei Jun; Lynch Christopher J; Newgard Christopher B; Buettner Christoph^*

来源：Cell Metabolism, 2014, 20(5): 898-909.

DOI：10.1016/j.cmet.2014.09.003

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 alpha-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.

• 出版日期2014-11-4