Short-term physical inactivity induces diacylglycerol accumulation and insulin resistance in muscle via lipin1 activation

• Published in: American journal of physiology: endocrinology and metabolism Vol. 321; no. 6; pp. E766 - E781
• Main Authors: Kakehi, Saori, Tamura, Yoshifumi, Ikeda, Shin-Ichi, Kaga, Naoko, Taka, Hikari, Ueno, Noriko, Shiuchi, Tetsuya, Kubota, Atsushi, Sakuraba, Keishoku, Kawamori, Ryuzo, Watada, Hirotaka
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2021
• Subjects: Accumulation; Adult; AKT protein; Animals; Casts, Surgical; Deoxyglucose; Diglycerides; Diglycerides - metabolism; Dogs; High fat diet; Hindlimb Suspension; Humans; Immobilization; Insulin; Insulin - metabolism; Insulin resistance; Insulin Resistance - physiology; Kinases; Lipids; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Phosphatidate Phosphatase - metabolism; Phosphatidic acid; Phosphorylation; Protein folding; Protein kinase C; Sedentary Behavior; Sensitivity enhancement; Signal transduction; Signal Transduction - physiology; Signaling; Soleus muscle; Time Factors; Young Adult; skeletal muscle; insulin resistance; intramyocellular lipid; physical inactivity
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00254.2020

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 HCI after HFD further increased it by 3.3-fold. Parallel to this, we found increased protein kinase C ε (PKCε) activity, reduced insulin-induced 2-deoxyglucose (2-DOG) uptake, and reduced phosphorylation of insulin receptor β (IRβ) and Akt, key molecules for insulin signaling pathway. Lipin1, which converts phosphatidic acid to diacylglycerol, showed increase of its activity by HCI, and dominant-negative lipin1 expression in muscle prevented HCI-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. 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.