MECHANISMS OF METABOLIC REGULATION BY DIETARY METHIONINE RESTRICTION

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，增强胰岛素敏感性。我们的数据提供了一个令人信服的案例，即饮食MR通过对能量平衡的中心介导作用和对外周组织的直接影响来重塑脂质代谢和增强胰岛素敏感性。我们假设，通过必需氨基酸依赖的信号和蛋氨酸对细胞谷胱甘肽的特异性作用，膳食MR的感知与这些反应相结合，从而增强胰岛素信号。我们将结合体内代谢表型和功能丧失动物模型的体外生化分析来检验必需氨基酸感知在各自对膳食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，以确定限制膳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能够检测蛋氨酸限制的营养传感和信号系统，并将这种饮食改变转化为高度整合和有益的生理反应。该提案提出的一个重要的未解决的问题是，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.