TY - JOUR TI - Valdecoxib improves lipid-induced skeletal muscle insulin resistance via simultaneous suppression of inflammation and endoplasmic reticulum stress AU - Kim, Tae Jin AU - Lee, Hyun Jung AU - Pyun, Do Hyeon AU - Abd El-Aty, A. M. AU - Jeong, Ji Hoon AU - Jung, Tae Woo T2 - Biochemical Pharmacology AB - Valdecoxib (VAL), a non-steroidal anti-inflammatory drug, has been widely used for treatment of rheumatoid arthritis, osteoarthritis, and menstrual pain. It is a selective cyclooxygenase-2 inhibitor. The suppressive effects of VAL on cardiovascular diseases and neuroinflammation have been documented; however, its impact on insulin signaling in skeletal muscle has not been studied in detail. The aim of this study was to investigate the effects of VAL on insulin resistance in mouse skeletal muscle. Treatment of C2C12 myocytes with VAL reversed palmitate-induced aggravation of insulin signaling and glucose uptake. Further, VAL attenuated palmitate-induced inflammation and endoplasmic reticulum (ER) stress in a concentration-dependent manner. Treatment with VAL concentration-dependently upregulated AMP-activated protein kinase (AMPK) and heat shock protein beta 1 (HSPB1) expression. In line with in vitro experiments, treatment with VAL augmented AMPK phosphorylation and HSPB1 expression, thereby alleviating high-fat diet-induced insulin resistance along with inflammation and ER stress in mouse skeletal muscle. However, small interfering RNA-mediated inhibition of AMPK abolished the effects of VAL on insulin resistance, inflammation, and ER stress. These results suggest that VAL alleviates insulin resistance through AMPK/HSPB1-mediated inhibition of inflammation and ER stress in skeletal muscle under hyperlipidemic conditions. Hence, VAL could be used as an effective pharmacotherapeutic agent for management of insulin resistance and type 2 diabetes. DA - 2021/06/01/ PY - 2021 DO - 10.1016/j.bcp.2021.114557 DP - ScienceDirect VL - 188 SP - 114557 J2 - Biochemical Pharmacology LA - en SN - 0006-2952 UR - https://www.sciencedirect.com/science/article/pii/S0006295221001532 Y2 - 2021/04/19/22:05:28 KW - AMPK KW - ER stress KW - HSPB1 KW - Inflammation KW - Insulin resistance KW - Valdecoxib ER -