School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, United States.
Front Endocrinol (Lausanne). 2021 Mar 31;12:651211. doi: 10.3389/fendo.2021.651211. eCollection 2021.
Lipid overload of the mitochondria is linked to the development of insulin resistance in skeletal muscle which may be a contributing factor to the progression of type 2 diabetes during obesity. The targeted degradation of mitochondria through autophagy, termed mitophagy, contributes to the mitochondrial adaptive response to changes in dietary fat. Our previous work demonstrates long-term (2-4 months) consumption of a high-fat diet increases mitochondrial lipid oxidation capacity but does not alter markers of mitophagy in mice. The purpose of this study was to investigate initial stages of mitochondrial respiratory adaptations to high-fat diet and the activation of mitophagy. C57BL/6J mice consumed either a low-fat diet (LFD, 10% fat) or high-fat diet (HFD, 60% fat) for 3 or 7 days. We measured skeletal muscle mitochondrial respiration and protein markers of mitophagy in a mitochondrial-enriched fraction of skeletal muscle. After 3 days of HFD, mice had lower lipid-supported oxidative phosphorylation alongside greater electron leak compared with the LFD group. After 7 days, there were no differences in mitochondrial respiration between diet groups. HFD mice had greater autophagosome formation potential (Beclin-1) and greater activation of mitochondrial autophagy receptors (Bnip3, p62) in isolated mitochondria, but no difference in downstream autophagosome (LC3II) or lysosome (Lamp1) abundance after both 3 and 7 days compared with the LFD groups. In cultured myotubes, palmitate treatment decreased mitochondrial membrane potential and hydrogen peroxide treatment increased accumulation of upstream mitophagy markers. We conclude that several days of high-fat feeding stimulated upstream activation of skeletal muscle mitophagy, potentially through lipid-induced oxidative stress, without downstream changes in respiration.
线粒体的脂质过载与骨骼肌胰岛素抵抗的发展有关，这可能是肥胖期间 2 型糖尿病进展的一个促成因素。通过自噬靶向降解线粒体，称为线粒体自噬，有助于线粒体对饮食脂肪变化的适应性反应。我们之前的工作表明，长期（2-4 个月）摄入高脂肪饮食会增加线粒体脂质氧化能力，但不会改变小鼠中线粒体自噬的标志物。本研究的目的是研究线粒体呼吸对高脂肪饮食的早期适应及其对线粒体自噬的激活。C57BL/6J 小鼠分别消耗低脂肪饮食（LFD，10%脂肪）或高脂肪饮食（HFD，60%脂肪）3 或 7 天。我们测量了骨骼肌线粒体呼吸和骨骼肌线粒体丰富部分中线粒体自噬的蛋白标志物。在 HFD 喂养 3 天后，与 LFD 组相比，小鼠的脂质支持氧化磷酸化能力降低，电子泄漏增加。在 7 天后，两组之间的线粒体呼吸没有差异。HFD 小鼠在分离的线粒体中具有更大的自噬体形成潜力（Beclin-1）和更大的线粒体自噬受体（Bnip3、p62）的激活，但与 LFD 组相比，在 3 天和 7 天后，下游自噬体（LC3II）或溶酶体（Lamp1）丰度没有差异。在培养的肌管中，软脂酸处理降低了线粒体膜电位，而过氧化氢处理增加了上游线粒体自噬标志物的积累。我们的结论是，几天的高脂肪喂养刺激了骨骼肌线粒体自噬的上游激活，可能是通过脂质诱导的氧化应激，而呼吸没有下游变化。
