Free fatty acid is considered one of the major pathogenic factors inducing insulin resistance. The association between iron disturbances and insulin resistance has recently begun to receive a lot of attention. Although skeletal muscle is a major tissue for iron utilization and storage, the role of iron in palmitate (PA)-induced insulin resistance is unknown.
We investigated the molecular mechanism underlying iron dysregulation in PA-induced insulin resistance. Intracellular iron was measured using calcein AM and transferrin-GFP. Iron and calcium chelator or siRNA were used to investigate the effects of iron metabolism on insulin sensitivity. Intracellular calcium was detected using Fluo-3 AM.
PA induced insulin resistance and simultaneously increased intracellular iron. The iron chelator, deferoxamine dramatically inhibited PA-induced insulin resistance, and iron donors impaired insulin sensitivity by activating JNK. PA upregulated tfR1 through IRP2. Knockdown of tfR1 and IRP2 prevented PA-induced iron uptake and insulin resistance. PA also translocated the tfR1-GFP protein complex by stimulating calcium influx, but the BAPTA-AM dramatically reduced iron overload by inhibiting transferrin translocation and subsequent insulin resistance. PA induces insulin resistance through iron overload, reducing intracellular iron protected cells against insulin resistance.
Therefore, blocking iron overload may be a useful strategy for preventing insulin resistance and diabetes.