<a>Leucine deprivation improves insulin sensitivity; however, whether and how this effect can be extended is unknown. We hypothesized that intermittent leucine deprivation (ILD) might produce a long-term effect on improved insulin sensitivity via the formation of metabolic memory. Consistently, seven ILD cycles treatment (1-day leucine-deficient diet, 3-day control diet) in mice produced a long-lasting (after resuming a control diet for 49 days) effect on improved whole-body and hepatic insulin

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... sensitivity in mice, indicating the potential formation of metabolic memory. Furthermore, the effects of ILD depended on hepatic general control nondepressible 2 (GCN2) expression as verified by gain-and loss-of-function experiments. Moreover, ILD increased <i>Gcn2 </i>expression by reducing its DNA methylation at two CpG promoter sites controlled by </a><a>demethylase</a> growth arrest and DNA damage inducible b. Finally, ILD also improved insulin sensitivity in insulin-resistant mice. Thus, ILD induces long-lasting improvements in insulin sensitivity by increasing hepatic <i>Gcn2</i> expression via a reduction in its DNA methylation. These results provide novel insights into understanding the link between leucine deprivation and insulin sensitivity, as well as potential nutritional intervention strategies for treating insulin resistance and related diseases. We also provide evidence for liver-specific metabolic memory after ILD and novel epigenetic mechanisms for <i>Gcn2</i> regulation.