Chinese Academy of Sciences China
Title: Mechanism for improved insulin sensitivity by branched-chain amino acids
Xiao Fei has completed her PhD and Postdoctoral studies from Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Her research interest is to understand the cellular and molecular mechanisms underlying genetic and nutritional regulation of metabolic diseases including obesity, diabetes, and fatty liver. She has published several papers in Diabetes, Diabetologia and Metabolism as first author.
We have previously shown that serum insulin levels decrease three-fold whereas blood glucose levels remain normal in mice fed leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the present study is to investigate this possibility and elucidate underlying mechanisms. Here it was shown that leucine deprivation improves hepatic insulin sensitivity by activating General Control Nonderepressible (GCN)2 and decreasing mammalian Target of Rapamycin (mTOR)/ ribosomal protein S6 kinase 1 (S6K1) signaling. Activation of AMP-activated protein kinase (AMPK) also contributes to this phenomenon. In addition, it was also shown that leucine deprivation improves insulin sensitivity under insulin-resistant conditions. This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation and demonstrates a novel function for GCN2 in the regulation of insulin sensitivity. Besides, it was found that valine or isoleucine deprivation for 7 days produces similar effects as leucine on insulin sensitivity regulated in a similar manner. Different from leucine, valine or isoleucine deprivation for 7 days significantly decreases fed blood glucose levels, possibly by decreasing expression of a key gluconeogenesis gene glucose-6-phosphatase. It was also found that insulin sensitivity is rapidly improved in mice following maintenance on a diet deficient for any individual BCAAs for 1 day. Results showed that the effect of leucine deprivation represents a general effect of BCAAs on regulation of insulin sensitivity, but not glucose levels, suggesting that each individual BCAA has unique feature in metabolic regulation. These observations also provide a rationale for short-term dietary deprivation or restriction of BCAAs for the treatment of insulin resistance and associated metabolic diseases.
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