MECHANISMS OF METABOLIC REGULATION BY DIETARY METHIONINE RESTRICTION

描述：饮食蛋氨酸限制(MR)产生一系列高度集成的生化和生理反应，以减少肥胖，改善代谢健康的生物标记物，并增强胰岛素敏感性。我们的数据提供了一个令人信服的案例，即饮食MR既通过对能量平衡的中枢调节作用，也通过对周围组织的直接作用来重塑脂肪代谢和增强胰岛素敏感性。我们假设，对饮食MR的感知是通过必要的氨基酸依赖信号和蛋氨酸对细胞谷胱甘肽的特异性作用的组合来耦合到这些反应中的，这有助于增强胰岛素信号。我们将使用体内代谢表型和体外生化分析与功能丧失动物模型相结合的方法来检验必需氨基酸感应在各自对膳食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建立限制膳食蛋氨酸相对于其他必需氨基酸的特异性。这项工作的目标是确定检测蛋氨酸限制的营养感知和信号系统，并将这种饮食改变转化为一套高度整合和有益的生理反应。这项提案解决的一个重大悬而未决的问题是，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好处。 公共卫生相关性：肥胖和代谢性疾病是世界上一个日益严重的健康问题，并使受影响的个人容易患上更严重的疾病，包括糖尿病、心脏病和中风。限制饮食蛋氨酸会产生一系列高度集成的生化和生理反应，从而减少肥胖，改善代谢健康的生物标记物，并增强胰岛素敏感性。本文建议的临床前研究是概念验证、测试和发现，以促进基于饮食的方法的发展，这些方法将转化为对代谢性疾病的有效治疗。

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. PUBLIC HEALTH RELEVANCE: Obesity and metabolic disease represent a growing health problem in the world and predispose affected individuals to developing more serious diseases including diabetes, heart disease, and stroke. Dietary methionine restriction produces a highly integrated series of biochemical and physiological responses that reduce adiposity, improve biomarkers of metabolic health and enhance insulin sensitivity. The pre-clinical studies proposed herein represent proof of concept testing and discovery to facilitate the development of diet-based approaches that will translate into effective treatments for metabolic disease.