Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Diabetes. 2022 Feb 1;71(2):206-218. doi: 10.2337/db21-0336.
Leucine deprivation improves insulin sensitivity; however, whether and how this effect can be extended are 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 of treatment (1-day leucine-deficient diet, 3-day control diet) in mice produced a long-lasting (after a control diet was resumed for 49 days) effect on improved whole-body and hepatic insulin 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 Gcn2 expression by reducing its DNA methylation at two CpG promoter sites controlled by demethylase 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 Gcn2 expression via a reduction in its DNA methylation. These results provide novel insights into understanding of 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 Gcn2 regulation.
亮氨酸缺乏可改善胰岛素敏感性；然而，这种效果是否以及如何能够持续尚不清楚。我们假设间歇性亮氨酸缺乏（ILD）可能通过形成代谢记忆对改善胰岛素敏感性产生长期影响。一致地，在小鼠中进行七次 ILD 治疗周期（1 天亮氨酸缺乏饮食，3 天对照饮食）产生了对小鼠全身和肝脏胰岛素敏感性的持久改善（在恢复对照饮食 49 天后）效果，表明代谢记忆的潜在形成。此外，ILD 的作用取决于肝通用控制不可抑制 2（GCN2）的表达，这通过增益和失能实验得到了验证。此外，ILD 通过减少其两个 CpG 启动子位点的 DNA 甲基化来增加 Gcn2 表达，该两个 CpG 启动子位点由去甲基酶生长抑制和 DNA 损伤诱导 b 控制。最后，ILD 还改善了胰岛素抵抗小鼠的胰岛素敏感性。因此，ILD 通过降低其 DNA 甲基化来增加肝 Gcn2 表达，从而诱导胰岛素敏感性的持久改善。这些结果为理解亮氨酸缺乏与胰岛素敏感性之间的联系以及治疗胰岛素抵抗和相关疾病的潜在营养干预策略提供了新的见解。我们还提供了 ILD 后肝脏特异性代谢记忆的证据和 Gcn2 调节的新的表观遗传机制。
