FOXO1 involvement in insulin resistance-related pro-inflammatory cytokine production in hepatocytes

Low-grade inflammation from hepatocytes plays a causal role in hepatic and systemic insulin resistance (IR). We aimed to explore whether and how FOXO1 was involved in IR-related inflammation in hepatocytes. We determined FOXO1 expression and activity, insulin and NF-kappa B signaling, and pro-inflammatory cytokine production in tumor necrosis factor-alpha (TNF-alpha)- or dexamethasone (DEX)-induced IR model in vitro and in high fat diet-induced obese or diabetic db/db mice in vivo with quantitative RT-PCR and Western blotting. We identified two different but physiologically relevant IR models characterized by attenuated insulin-induced phosphorylation of insulin receptor substrate-1 and AKT in TNF-alpha- or DEX-treated HepG2 cells. DEX largely increased FOXO1 expression in hepatocytes, while TNF-alpha did not. Notably, FOXO1 phosphorylation was attenuated in both models. TNF-alpha-stimulated nuclear translocation of NF-kappa B (p65) and mRNA levels of interleukin (IL)-1, IL-6 and monocyte attractant protein-1 were partly blocked, while the anti-inflammatory role of DEX was largely potentiated by insulin. FOXO1 knockdown by human-specific FOXO1 small interfering RNA exerted an identical role to insulin. Furthermore, augmented hepatic FOXO1 expression and decreased phosphorylation were found to be associated with elevated pro-inflammatory cytokine production in high fat diet-induced obese and db/db mice. FOXO1 potentiates pro-inflammatory cytokine production in insulin-resistant hepatocytes.