Revealing the contribution of iron overload-brown adipocytes to iron overload cardiomyopathy: Insights from RNA-seq and exosomes coculture technology.

Iron overload has been demonstrated to be associated with insulin resistance, iron overload cardiomyopathy (IOC). Brown adipose tissue (BAT) is emerging as a novel therapeutic target for the treatment of various diseases, not only because of its capacity for dissipating excess energy via non-shivering thermogenesis, but also because of its implication in physiological and pathophysiological processes. However, little attention has been devoted to the precise alterations and impacts of iron overload-BAT. We conducted RNA-Seq analysis on BAT samples obtained from mice subjected to a high iron diet (HID) or a normal chow diet (CON), respectively. The RNA-seq transcriptomic analysis revealed that 1,289 differentially expressed RNAs (DEGs) were identified, with a higher number of the downregulated genes (910 genes) compared to the upregulated genes (379 genes). The results of Gene Ontology (GO) and The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the downregulated DEGs were primarily involved in hypertrophic cardiomyopathy, dilated cardiomyopathy, which were defined as IOC under the iron overload condition. The association between iron overload-BAT with cardiomyopathy was further investigated using exosome coculture technology. Our results demonstrated that the exosomes derived from ferric citrate treated-mature HIB 1B brown adipocytes, could be internalized by HL-1 cardiomyocytes, and contributed to the dysfunction in these cells. The present study has revealed the alterations and impacts of iron overload-BAT, particularly on the onset of IOC via not only RNA-seq but also exosomes coculture technology. The outputs might shed light on the novel therapeutic strategies for the treatment of IOC.