Stone Kirsten P, Wanders Desiree, Orgeron Manda, Cortez Cory C, Gettys Thomas W
Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA
Diabetes. 2014 Nov;63(11):3721-33. doi: 10.2337/db14-0464. Epub 2014 Jun 19.
To understand the physiological significance of the reduction in fasting insulin produced by dietary methionine restriction (MR), hyperinsulinemic-euglycemic clamps were used to examine the effect of the diet on overall and tissue-specific insulin sensitivity in mice. The steady-state glucose infusion rate was threefold higher in the MR group and consistent with the 2.5- to threefold increase in 2-deoxyglucose uptake in skeletal muscle, heart, and white adipose tissue. Dietary MR enhanced suppression of hepatic glucose production by insulin, enhanced insulin-dependent Akt phosphorylation in the liver, and increased hepatic expression and circulating fibroblast growth factor 21 (FGF-21) by fourfold. Limitation of media methionine recapitulated amplification of Akt phosphorylation by insulin in HepG2 cells but not in 3T3-L1 adipocytes or C2C12 myotubes. Amplification of insulin signaling in HepG2 cells by MR was associated with reduced glutathione, where it functions as a cofactor for phosphatase and tensin homolog. In contrast, FGF-21, but not restricting media methionine, enhanced insulin-dependent Akt phosphorylation in 3T3-L1 adipocytes. These findings provide a potential mechanism for the diet-induced increase in insulin sensitivity among tissues that involves a direct effect of methionine in liver and an indirect effect in adipose tissue through MR-dependent increases in hepatic transcription and release of FGF-21.
为了解饮食中蛋氨酸限制（MR）导致空腹胰岛素降低的生理意义，采用高胰岛素-正常血糖钳夹技术来检测该饮食对小鼠整体及组织特异性胰岛素敏感性的影响。MR组的稳态葡萄糖输注率高出三倍，这与骨骼肌、心脏和白色脂肪组织中2-脱氧葡萄糖摄取增加2.5至三倍相一致。饮食MR增强了胰岛素对肝葡萄糖生成的抑制作用，增强了肝脏中胰岛素依赖性Akt磷酸化，并使肝脏中纤维母细胞生长因子21（FGF-21）的表达和循环水平增加了四倍。培养基中蛋氨酸的限制在HepG2细胞中重现了胰岛素对Akt磷酸化的放大作用，但在3T3-L1脂肪细胞或C2C12肌管中则未出现这种情况。MR对HepG2细胞中胰岛素信号的放大作用与谷胱甘肽减少有关，谷胱甘肽在其中作为磷酸酶和张力蛋白同源物的辅助因子发挥作用。相比之下，FGF-21而非培养基中蛋氨酸的限制增强了3T3-L1脂肪细胞中胰岛素依赖性Akt磷酸化。这些发现为饮食诱导的组织胰岛素敏感性增加提供了一种潜在机制，该机制涉及蛋氨酸在肝脏中的直接作用以及通过MR依赖性增加肝脏中FGF-21的转录和释放而在脂肪组织中的间接作用。
