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Abstract：
Bariatric surgery provides significant and durable improvements in glycemic control and hepatic steatosis, but the underlying mechanisms that drive improvements in these metabolic parameters remain to be fully elucidated. Recently, alterations in mitochondrial morphology have shown a direct link to nutrient adaptations in obesity. Here, we evaluate the effects of Roux-en-Y gastric bypass (RYGB) surgery on markers of liver mitochondrial dynamics in a diet-induced obesity Sprague-Dawley (SD) rat model. Livers were harvested from adult male SD rats 90-days after either Sham or RYGB surgery and continuous high-fat feeding. We assessed expression of mitochondrial proteins involved in fusion, fission, mitochondrial autophagy (mitophagy) and biogenesis, as well as differences in citrate synthase activity and markers of oxidative stress. Gene expression for mitochondrial fusion genes, mitofusin 1 (Mfn1; P < 0.05), mitofusin 2 (Mfn2; P < 0.01), and optic atrophy 1 (OPA1; P < 0.05) increased following RYGB surgery. Biogenesis regulators, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α; P < 0.01) and nuclear respiratory factor 1 (Nrf1; P < 0.05), also increased in the RYGB group, as well as mitophagy marker, BCL-2 interacting protein 3 (Bnip3; P < 0.01). Protein expression for Mfn1 (P < 0.001), PGC1α (P < 0.05), BNIP3 (P < 0.0001), and mitochondrial complexes I-V (P < 0.01) was also increased by RYGB, and Mfn1 expression negatively correlated with body weight, insulin resistance, and fasting plasma insulin. In the RYGB group, citrate synthase activity was increased (P < 0.02) and reactive oxygen species (ROS) was decreased compared to the Sham control group (P < 0.05), although total antioxidant capacity was unchanged between groups. These data are the first to show an association between RYGB surgery and improved markers of liver mitochondrial dynamics. These observed improvements may be related to weight loss and reduced energetic demand on the liver, which could facilitate normalization of glucose homeostasis and protect against hepatic steatosis.
摘要：
减肥手术在血糖控制和肝脏脂肪变性方面提供了显著和持久的改善，但推动这些代谢参数改善的潜在机制仍有待完全阐明.最近,线粒体形态的改变已显示与肥胖患者的营养适应有直接联系.这里,我们评估了Roux-en-Y胃旁路术(RYGB)手术对饮食诱导的肥胖Sprague-Dawley(SD)大鼠模型中肝脏线粒体动力学标志物的影响.在Sham或RYGB手术和连续高脂肪喂养后90天，从成年雄性SD大鼠中收获肝脏。我们评估了参与融合的线粒体蛋白的表达，裂变,线粒体自噬（线粒体自噬）和生物发生，以及柠檬酸合酶活性和氧化应激标志物的差异。线粒体融合基因的基因表达，mitofusin1（Mfn1；P<0.05），mitofusin2（Mfn2；P<0.01），视神经萎缩1（OPA1；P<0.05）在RYGB手术后增加。生物发生调节剂，过氧化物酶体增殖物激活受体γ-辅激活因子1-α(PGC1α;P<0.01)和核呼吸因子1(Nrf1;P<0.05),在RYGB组中也有所增加，以及线粒体自噬标记，BCL-2相互作用蛋白3(Bnip3;P<0.01)。Mfn1的蛋白表达（P<0.001），PGC1α（P<0.05），BNIP3（P<0.0001），线粒体复合物I-V（P<0.01）也增加了RYGB，Mfn1表达与体重呈负相关，胰岛素抵抗，和空腹血浆胰岛素。在RYGB组中,与假手术对照组相比，柠檬酸合酶活性增加（P<0.02），活性氧（ROS）减少（P<0.05），尽管总抗氧化能力在组间没有变化。这些数据是第一个显示RYGB手术和改善的肝线粒体动力学标志物之间的关联。这些观察到的改善可能与体重减轻和肝脏能量需求减少有关，这可以促进葡萄糖稳态的正常化并防止肝脏脂肪变性。
