TiO2 nanoparticles induce insulin resistance in liver-derived cells both directly and via macrophage activation

Upon exposure, TiO2 nanoparticles (NPs) have been recovered in internal organs such as the liver, and are proposed to cause cellular/organ dysfunction, particularly in the liver and lungs. We hypothesized that despite being considered "inert" as bulk material, TiO2 NPs may impair insulin responses in liver-derived cells, either indirectly by inflammatory activation of macrophages, and/or by directly interfering with insulin signaling. Using qRT-PCR and conditioned medium (CM) approaches, we show that exposure to TiO2 NPs activates macrophages' expression of TNF-alpha, IL-6, IL-8, IL-1 alpha and IL-1 beta and the resulting CM induces insulin resistance in Fao cells. Furthermore, direct exposure of Fao cells to TiO2 results in activation of the stress kinases JNK and p38MAP kinase, and in induction of insulin resistance at the signaling and metabolic levels. Collectively, our findings provide a proof-of-concept for the ability of man-made NPs to induce insulin resistance in liver-derived cells, an endocrine abnormality underlying some of the most common human diseases.