Mechanisms of Metabolic Regulation by Dietary Methionine Restriction

膳食蛋氨酸限制(MR)产生一系列高度集成的生化和 减少肥胖、改善代谢健康的生物标志物和 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，饮食MR通过两者发挥作用 中枢调节对能量平衡的影响，以及对周围组织的直接影响 重塑白色脂肪组织，激活棕色脂肪组织的产热作用，并增强 胰岛素敏感性。我们假设，对饮食MR的感觉与这些反应有关 通过肝脏感知还原型蛋氨酸通过谷胱甘肽依赖机制 这激活了CREBH和eIF2激酶，PERK。CREBH和PERK结果的激活 激活eif2、α和nrf2依赖的转录程序，增加肝脏 FGF21的表达和释放。我们假设FGF21的增加通过 直接和中央调节的机制，激活生热，增加能量 消耗，减少脂肪沉积，并提高整体胰岛素敏感性。我们将使用 体内代谢表型和体外生化分析相结合的研究 功能动物模型研究必需氨基酸感觉在各自的 对饮食MR的反应这项工作的目标是识别营养感应和信号传递 检测蛋氨酸限制并将这种饮食改变转化为 高度集成和有益的一组生理反应。

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 white adipose tissue, activate thermogenesis in brown adipose tissue, and enhance insulin sensitivity. We hypothesize that sensing of dietary MR is coupled to these responses through hepatic sensing of reduced methionine through a glutathione-dependent mechanism that activates CREBH and the eIF2 kinase, PERK. The activation of CREBH and PERK results in activation eIF2α- and NRF2-dependent transcriptional programs that increase hepatic expression and release of FGF21. We hypothesize that the increase in FGF21 acts through direct and centrally-mediated mechanisms to activate thermogenesis, increase energy expenditure, reduce fat deposition, and enhance overall insulin sensitivity. 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. 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.