Moderate iron restriction improves metabolism via epigenetic regulation of GDF15.

Iron overload disrupts endocrine function and metabolic health, while iron chelation and phlebotomy enhance metabolic fitness in humans and mice. However, the working mechanism of iron-lowering strategies remains largely undefined, and it is unclear whether dietary iron restriction can serve as a new strategy to treat metabolic syndrome. Here we show that 20-ppm iron (i.e., iron moderately restricted) diet increased insulin sensitivity, adipose mitochondrial biogenesis, and energy expenditure compared to 50-ppm iron (i.e., iron adequate) diet in mice. By contrast, severe iron restriction (4-ppm iron diet) caused anemia, underweight and metabolic disorder. Mechanistically, moderate iron restriction induced a condition of subcellular "iron deficiency" due to iron redistribution into mitochondria in adipose tissues, which augmented H3K4 methylation possibly by suppressing iron-dependent histone demethylase like JARID. Enriched H3K4 methylation upregulated the expression of GDF15, a nutrient sensor that promotes adipose browning and metabolic enhancement. Pharmacological inhibition of H3K4 methylation or knockdown of GDF15 prevented iron restriction-induced enhancement of insulin sensitivity. Our study reveals a potential strategy targeting dietary iron to prevent metabolic disorder. It provides the first line of evidence of epigenetic regulation of GDF15 via an iron restriction-H3K4 methylation cascade. Future studies of the H3K4 methylation-GDF15 axis may fuel developing therapeutic options or dietary interventions for metabolic disease.