MyD88 缺失可保护雌性小鼠免于因不活动引起的肥胖和胰岛素抵抗。
Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity-Induced Adiposity and Insulin Resistance.
机构信息
Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City, Utah, USA.
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, USA.
出版信息
Obesity (Silver Spring). 2020 Apr;28(4):772-782. doi: 10.1002/oby.22759. Epub 2020 Feb 28.
OBJECTIVE
Inactivity and inflammation are linked to obesity and insulin resistance. It was hypothesized that MyD88 (mediates inflammation) knockout from muscle (MusMyD88 ) would prevent, whereas miR146a (MyD88 inhibitor) would exacerbate, inactivity-induced metabolic disturbances.
METHODS
Cre-control, MusMyD88 , and miR146a mice were given running wheels for 5 weeks to model an active phenotype. Afterward, half were placed into a small mouse cage (SMC) to restrict movement for 8 days. Body composition, muscle ( H)2-deoxyglucose uptake, visceral fat histology, and tissue weight (hind limb muscles, visceral fat, and liver) were assessed. In skeletal muscle and visceral fat, RNA sequencing and mitochondrial function were performed on female MusMyD88 and Cre-control SMC mice.
RESULTS
The SMC induced adiposity, hyperinsulinemia, and muscle insulin-stimulated glucose uptake, which was worsened in miR146a mice. In females, MusMyD88 mice were protected. Female MusMyD88 mice during the SMC period (vs. Cre-control) exhibited higher Igf1 and decreased Ip6k3 and Trim63 muscle expression. Visceral fat transcript changes corresponded to improved lipid metabolism, decreased adipose expansion (Gulp1↑, Anxa2↓, Ehd1↓) and meta-inflammation (Hmox1↓), and increased beiging (Fgf10↑). Ralgapa2, negative regulator of GLUT4 translocation, and inflammation-related gene 993011J21Rik2 were decreased in both muscle and fat.
CONCLUSIONS
Whole-body miR146a exacerbated inactivity-induced fat gain and muscle insulin resistance, whereas MusMyD88 prevented insulin resistance in female mice.
目的
不活动和炎症与肥胖和胰岛素抵抗有关。据推测，肌肉中的 MyD88（炎症介质）敲除（MusMyD88）将预防，而 miR146a（MyD88 抑制剂）将加剧不活动引起的代谢紊乱。
方法
给予 Cre 对照、MusMyD88 和 miR146a 小鼠 5 周跑步轮以模拟活跃表型。之后，将一半小鼠放入小老鼠笼（SMC）中以限制运动 8 天。评估身体成分、肌肉（H）2-脱氧葡萄糖摄取、内脏脂肪组织学和组织重量（后肢肌肉、内脏脂肪和肝脏）。在骨骼肌和内脏脂肪中，对雌性 MusMyD88 和 Cre 对照 SMC 小鼠进行 RNA 测序和线粒体功能分析。
结果
SMC 引起肥胖、高胰岛素血症和肌肉胰岛素刺激的葡萄糖摄取，而 miR146a 小鼠则加重。在女性中，MusMyD88 小鼠受到保护。在 SMC 期间（与 Cre 对照相比），MusMyD88 雌性小鼠表现出更高的 Igf1 和更低的 Ip6k3 和 Trim63 肌肉表达。内脏脂肪转录变化与改善脂质代谢、减少脂肪扩张（Gulp1↑、Anxa2↓、Ehd1↓）和代谢炎症（Hmox1↓）以及增加米色形成（Fgf10↑）相对应。Ralgapa2，GLUT4 易位的负调节剂和炎症相关基因 993011J21Rik2 在肌肉和脂肪中均减少。
结论
全身 miR146a 加剧了不活动引起的脂肪增加和肌肉胰岛素抵抗，而 MusMyD88 则防止了雌性小鼠的胰岛素抵抗。
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