IGFBP5 Suppresses Oleate-induced Intramyocellular Lipids Deposition and Enhances Insulin Signaling

Excess intramyocellular lipids are often accompanied by muscle insulin resistance (IR) and type 2 diabetes. The mechanism of the formation of intramyocellular lipids is unclear yet. In this study, we optimized the cellular model of intramyocellular lipids from differentiated C2C12 cells and identified that the expression of insulin-like growth factor-binding protein 5 (IGFBP5) is diminished in this process. Then, we added exogenous recombinant IGFBP5 during myocyte triglyceride (TAG) formation and found decreased lipids accumulation. In addition, IGFBP5 could promote lipolysis when added to the cellular model after the formation of intramyocellular lipids. Moreover, IGFBP5 could enhance myocyte insulin sensitivity by inhibiting the expression of the thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4), which are a negative regulator of insulin signaling in both cases. Meanwhile, IGFBP5 also inhibited the expression of glycerol-3-phosphate acyltransferase (GPAM) and diglyceride acyltransferase 2 (DGAT2), which were involved in TAG synthesis from a fatty acid. IGFBP5 also reduced TAG storage by promoting lipolysis. Therefore, IGFBP5 may play a role in the excess accumulation of lipid in muscle cells of diabetic patients and serve as a reference for further research and treatment of muscle IR and diabetes.