Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism
Circulating branched-chain amino acid (BCAA) levels are elevated in obesity and 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 protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway in the liver. Selective induction of hypothalamic insulin signaling in rats as well as inducible and lifelong genetic modulation of brain insulin receptor expression in mice both demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Further, short-term overfeeding impairs the ability of brain insulin to lower circulating BCAA levels in rats. Chronic high-fat feeding in primates and obesity and/or type 2 diabetes in humans is associated with reduced BCKDH protein expression in liver, further supporting the concept that decreased hepatic BCKDH is a primary cause of increased plasma BCAA levels in insulin-resistant states. These findings demonstrate that neuroendocrine pathways control BCAA homeostasis and that hypothalamic insulin resistance can be a cause of impaired BCAA metabolism in obesity and diabetes.
- Research Organization:
- Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)
- Sponsoring Organization:
- USDOE; National Institutes of Health (NIH)
- Grant/Contract Number:
- AC05-76RLO 1830; AC05-76RL01830; DK074873; DK083568; DK082724; K01 DK099463; P51 OD011092; P41 GM103493
- OSTI ID:
- 1227559
- Alternate ID(s):
- OSTI ID: 1166866
- Report Number(s):
- PNNL-SA-103823; S1550413114004008; PII: S1550413114004008
- Journal Information:
- Cell Metabolism, Journal Name: Cell Metabolism Vol. 20 Journal Issue: 5; ISSN 1550-4131
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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