Exercise ameliorates nonalcoholic fatty liver disease by reducing the IGFBP5 to IGF1 ratio to activate AMPK pathway

Insulin-like growth factor-binding protein 5 (IGFBP5) is associated with nonalcoholic fatty liver disease (NAFLD). IGFBP5 has a higher binding affinity to IGF1 and modulates its effects in serum. However, the effect of exercise on its expression remains unclear. Hence, this study investigated whether exercise regulated hepatic and circulating IGFBP5 levels to ameliorate NAFLD. The NAFLD mice were regularly trained for 12 weeks on a treadmill at a 0% grade. Serum levels of IGFBP5, total IGF1, and free IGF1 were detected using proteome analyses and ELISA. Critical cytokines, such as IRS1, Akt, and AMPKα, and their phosphorylation levels mediated by IGFBP5/IGF1 were confirmed via Western blotting. The results indicated that exercise remarkably alleviated HFD-induced NAFLD and insulin resistance. Although exercise lowered serum IGFBP5 levels and the IGFBP5/total IGF1 ratio in NAFLD mice, it had no effect on the hepatic expression of IGFBP5, IGF1, and IGF1R. Moreover, exercise increased serum levels of free IGF1 in NAFLD mice, which, when bound to IGF1R, accelerated the phosphorylation levels of hepatic IRS1, Akt, and AMPKα to ameliorate NAFLD. The present study confirmed that exercise activated the effects of IGF1 by reducing the serum IGFBP5/IGF1 ratio, consequently triggering the IRS1/Akt/AMPK pathway to ameliorate HFD-induced NAFLD.