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。我们的数据提出了一个令人信服的案例，即饮食MR通过以下两种途径起作用： 对能量平衡的中枢介导作用，以及对外周组织的直接作用， 重塑白色脂肪组织，激活棕色脂肪组织中的产热，并增强 胰岛素敏感性我们假设饮食MR的感知与这些反应有关 通过谷胱甘肽依赖性机制通过肝脏感知还原蛋氨酸 激活CREBH和eIF2激酶PERK。CREBH和PERK的激活导致 在激活eIF2α和NRF2依赖性转录程序中， FGF21的表达和释放。我们假设FGF21的增加是通过 直接和中枢介导的机制，以激活产热，增加能量 消耗，减少脂肪沉积，并提高整体胰岛素敏感性。我们将使用一个 体内代谢表型分析和离体生物化学分析的组合， 功能动物模型，以检查必需氨基酸传感在相应的 这项工作的目标是确定营养感应和信号传导 检测甲硫氨酸的限制并将这种饮食改变转化为 高度整合和有益的生理反应。

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.