Department of Endocrinology and Nutrition, University Hospital Doctor Peset-FISABIO, Avda. Gaspar Aguilar 90, 46017 Valencia, Spain.
Department of Endocrinology and Nutrition, University Hospital Doctor Peset-FISABIO, Avda. Gaspar Aguilar 90, 46017 Valencia, Spain; CIBER CB06/04/0071 Research Group, CIBER Hepatic and Digestive Diseases, University of Valencia, Av Blasco Ibáñez 13, 46010 Valencia, Spain; Department of Physiology, University of Valencia, Av Blasco Ibáñez 13, 46010 Valencia, Spain.
Mol Metab. 2019 Jan;19:24-33. doi: 10.1016/j.molmet.2018.10.005. Epub 2018 Oct 19.
In obese patients undergoing caloric restriction, there are several potential mechanisms involved in the improvement of metabolic outcomes. The present study further explores whether caloric restriction can modulate endoplasmic reticulum (ER) stress and mitochondrial function, as both are known to be mechanisms underlying inflammation and insulin resistance (IR) during obesity.
A total of 64 obese patients with BMI ≥35 kg/m underwent a dietary program consisting of 6 weeks of a very-low-calorie diet followed by 18 weeks of low-calorie diet. We evaluated changes in the metabolic and inflammatory markers -TNFα, hsCRP, complement component 3 (C3c), and retinol binding protein 4 (RBP4)-, in the ER stress markers and modulators -eIF2α-P, sXBP1, ATF6, JNK-P, CHOP, GRP78, and SIRT1-, and in mitochondrial function parameters -mitochondrial reactive oxygen species (mROS), glutathione peroxidase 1 (GPX1), cytosolic Ca, and mitochondrial membrane potential.
The dietary intervention produced an 8.85% weight loss associated with enhanced insulin sensitivity, a less marked atherogenic lipid profile, and a decrease in systemic inflammation (TNFα, hsCRP) and adipokine levels (RBP4 and C3c). Chronic ER stress was significantly reduced (ATF6-CHOP, JNK-P) and expression levels of SIRT1 and GRP78 - a Ca-dependent chaperone - were increased and accompanied by the restoration of Ca depots. Furthermore, mROS production and mitochondrial membrane potential improvement were associated with the up-regulation of the antioxidant enzyme GPX1.
Our data provide evidence that moderate weight loss attenuates systemic inflammation and IR and promotes the amelioration of ER stress and mitochondrial dysfunction, increasing the expression of chaperones, SIRT1 and antioxidant GPX1.
在接受热量限制的肥胖患者中，有几种潜在的机制可以改善代谢结果。本研究进一步探讨热量限制是否可以调节内质网（ER）应激和线粒体功能，因为这两者都已知是肥胖期间炎症和胰岛素抵抗（IR）的机制。
共有 64 名 BMI≥35kg/m2 的肥胖患者接受了饮食计划，该计划包括 6 周的极低热量饮食和 18 周的低热量饮食。我们评估了代谢和炎症标志物-TNFα、hsCRP、补体成分 3（C3c）和视黄醇结合蛋白 4（RBP4）-、内质网应激标志物和调节剂-eIF2α-P、sXBP1、ATF6、JNK-P、CHOP、GRP78 和 SIRT1-以及线粒体功能参数-线粒体活性氧（mROS）、谷胱甘肽过氧化物酶 1（GPX1）、胞质 Ca 和线粒体膜电位的变化。
饮食干预导致体重减轻 8.85%，伴随胰岛素敏感性增强、脂质谱致动脉粥样硬化程度降低、全身炎症（TNFα、hsCRP）和脂肪因子水平（RBP4 和 C3c）降低。慢性 ER 应激显著降低（ATF6-CHOP、JNK-P），SIRT1 和 GRP78（一种 Ca 依赖性伴侣）的表达水平增加，Ca 库得到恢复。此外，mROS 产生和线粒体膜电位的改善与抗氧化酶 GPX1 的上调有关。
我们的数据提供了证据表明，适度的体重减轻可以减轻全身炎症和 IR，并促进 ER 应激和线粒体功能障碍的改善，增加伴侣蛋白、SIRT1 和抗氧化酶 GPX1 的表达。
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