MECHANISMS OF METABOLIC REGULATION BY DIETARY METHIONINE RESTRICTION

产品说明：饮食蛋氨酸限制（MR）产生一系列高度整合的生化和生理反应，减少肥胖，改善代谢健康的生物标志物，提高胰岛素敏感性。我们的数据使一个令人信服的情况下，饮食MR通过中央介导的影响能量平衡，并直接影响外周组织，重塑脂质代谢和提高胰岛素敏感性。我们假设，通过必需氨基酸依赖性信号传导和对细胞谷胱甘肽的甲硫氨酸特异性作用（其用于增强胰岛素信号传导）的组合，饮食MR的感测与这些反应偶联。我们将使用体内代谢表型和离体生物化学分析与功能丧失的动物模型相结合，以检查必需氨基酸传感在各自对饮食MR的反应中的作用。这些研究将通过体内和体外双管齐下的方法来补充，以建立限制饮食蛋氨酸与其他必需氨基酸的特异性。这项工作的目标是确定营养传感和信号系统，检测甲硫氨酸的限制，并将这种饮食调整转化为一个高度集成和有益的生理反应。该提案解决的重要未回答的问题是，与限制其他必需氨基酸相比，限制蛋氨酸是否以及如何提供显著的额外益处。

DESCRIPTION: Dietary methionine restriction (MR) produces a highly integrated series of biochemical and physiological responses that reduce adiposity, improve biomarkers of metabolic health and enhance insulin sensitivity. Our data make a compelling case that dietary MR acts through both centrally-mediated effects on energy balance, and direct effects on peripheral tissues that remodel lipid metabolism and enhance insulin sensitivity. We hypothesize that sensing of dietary MR is coupled to these responses through a combination of essential amino acid- dependent signaling and methionine-specific effects on cell glutathione which serve to enhance insulin signaling. We will use a combination of in vivo metabolic phenotyping and ex vivo biochemical analysis with loss of function animal models to examine the role of essential amino acid sensing in the respective responses to dietary MR. These studies will be complemented by a two-pronged in vivo and in vitro approach to establish the specificity of restricting dietary methionine versus other essential amino acids. The goal of this work is to identify the nutrient sensing and signaling systems which detect the restriction of methionine and translate this dietary modification into a highly integrated and beneficial set of physiological responses. The significant unanswered question addressed by this proposal is whether and how restriction of methionine provides significant additional benefits compared to restriction other essential amino acids.