Short-term physical inactivity induces diacylglycerol accumulation and insulin resistance in muscle via lipin1 activation
Short-term physical inactivity induces diacylglycerol accumulation and insulin resistance in muscle via lipin1 activation
复制标题
DOI：
10.1152/ajpendo.00254.2020
复制
发表时间：
2021-12-01
影响因子：
5.1
通讯作者：
Watada, Hirotaka
中科院分区：
文献类型：
--
作者：
Kakehi, Saori;Tamura, Yoshifumi;Watada, Hirotaka
缺乏体力活动会损害肌肉胰岛素敏感性。然而，其机制尚不清楚。为了模拟身体不活动，我们对正常或高脂饮食（HFD）的小鼠进行了24小时后肢石膏固定（HCI），并评估了比目鱼肌中的肌细胞内脂质和胰岛素信号通路。虽然2周HFD单独没有改变肌细胞内二酰甘油（IMDG）的积累，盐酸单独增加了1.9倍，盐酸HFD后进一步增加了3.3倍。与此同时，我们发现蛋白激酶C β（PKC β）活性增加，胰岛素诱导的2-脱氧葡萄糖（2-DOG）摄取减少，胰岛素受体β（IR β）和Akt（胰岛素信号通路的关键分子）磷酸化减少。Lipin 1，它将磷脂酸转化为二酰甘油，表现出增加其活性的盐酸，和显性负lipin 1在肌肉中的表达，防止盐酸诱导的IMDG积累和受损的胰岛素诱导的2-DOG摄取。此外，24小时腿石膏固定在人类增加lipin 1的表达。因此，即使是短期的固定也会增加IMDG，并通过增强lipin 1活性来损害肌肉中的胰岛素敏感性。然而，其机制尚不清楚。为了模拟身体不活动，我们对正常或高脂肪饮食的小鼠进行24小时后肢石膏固定，并评估比目鱼肌中的肌细胞内脂质和胰岛素信号通路。我们发现，即使是短期的固定增加肌细胞内的甘油二酯，并通过增强lipin 1活性损害肌肉中的胰岛素敏感性。
Physical inactivity impairs muscle insulin sensitivity. However, its mechanism is unclear. To model physical inactivity, we applied 24-h hind-limb cast immobilization (HCI) to mice with normal or high-fat diet (HFD) and evaluated intramyocellular lipids and the insulin signaling pathway in the soleus muscle. Although 2-wk HFD alone did not alter intramyocellular diacylglycerol (IMDG) accumulation, HCI alone increased it by 1.9-fold and HCl after HFD further increased it by 3.3-fold. Parallel to this, we found increased protein kinase C epsilon (PKC epsilon) activity, reduced insulin-induced 2-deoxyglucose (2-DOG) uptake, and reduced phosphorylation of insulin receptor beta (IR beta) and Akt, key molecules for insulin signaling pathway. Lipin1, which converts phosphatidic acid to diacylglycerol, showed increase of its activity by HCl, and dominant-negative lipin1 expression in muscle prevented HCl-induced IMDG accumulation and impaired insulin-induced 2-DOG uptake. Furthermore, 24-h leg cast immobilization in human increased lipin1 expression. Thus, even short-term immobilization increases IMDG and impairs insulin sensitivity in muscle via enhanced lipin1 activity.NEW & NOTEWORTHY Physical inactivity impairs muscle insulin sensitivity. However, its mechanism is unclear. To model physical inactivity, we applied 24-h hind-limb cast immobilization to mice with normal or high-fat diet and evaluated intramyocellular lipids and the insulin signaling pathway in the soleus muscle. We found that even short-term immobilization increases intramyocellular diacylglycerol and impairs insulin sensitivity in muscle via enhanced lipin1 activity.