Endocrinology

Biography

Biography: Andrew C Shin

Abstract

Circulating branched-chain amino acid (BCAA) levels are elevated in obese and diabetic individuals, and are the earliest and most predictive marker for risk of diabetes. Furthermore, supplementation of amino acids or BCAAs has been shown to induce insulin resistance in rodents and humans, implicating BCAAs in the pathogenesis of diabetes. Thus, identifying the regulatory mechanisms of BCAAs is critical for understanding their rise seen in obese and/or diabetes. We have shown that insulin dose-dependently lowers plasma BCAAs while glucose per se does not seem to be an important regulator of BCAA metabolism. Insulin induced the hepatic expression and activity of branched-chain α keto-acid dehydrogenase (BCKDH), the rate-limiting enzyme in BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats as well as inducible and lifelong genetic modulation of brain insulin receptors in mice demonstrated that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Further, short-term overfeeding impaired the ability of brain insulin to lower circulating BCAA levels in rats. Chronic high-fat feeding in non-human primates and obesity and/or diabetes in humans were associated with reduced hepatic BCKDH protein expression. Lastly, C. elegans that lack insulin receptor homologue (Daf-2) in neurons showed increased BCAAs. These findings demonstrate that neuroendocrine pathways control BCAA homeostasis and these are evolutionarily conserved from worms to mammals. The findings also suggest that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes, and that plasma BCAAs may be a marker for hypothalamic insulin action.