Deletion of H-ferritin in macrophages alleviates obesity and diabetes induced by high-fat diet in mice

Aims/hypothesis
Iron accumulation affects obesity and diabetes, both of which are ameliorated by iron reduction. Ferritin, an iron storage protein, plays a crucial role in iron metabolism. H-ferritin exerts its cytoprotective action by reducing toxicity via its ferroxidase activity. We investigated the role of macrophage H-ferritin in obesity and diabetes.
Methods
Conditional macrophage-specific H-ferritin knockout (LysM-Cre FthKO) mice were used and divided into 4 groups; Wild-type (WT) and LysM-Cre FthKO mice with normal diet (ND), and WT and LysM-Cre Fth-KO mice with high-fat diet (HFD).
Results
Iron concentration reduced, and mRNA expression of ferroportin increased in macrophages from LysM-Cre FthKO mice. HFD-induced obesity was lower in LysM-Cre FthKO mice than in WT mice at 12 weeks (body weight (g); KO 34.6 ± 5.6 vs. WT 40.1 ± 5.2). mRNA expression of inflammatory cytokines, infiltrated macrophages, and oxidative stress increased in the adipose tissue of WT mice with HFD, but was not elevated in LysM-Cre FthKO mice with HFD. However, WT mice with HFD had elevated iron concentration in adipose tissue and spleen, which was not observed in LysM-Cre FthKO mice with HFD (adipose (μmol Fe/g protein); KO 1496 ± 479 vs. WT 2316 ± 866, spleen (μmol Fe/g protein); KO 218 ± 54 vs. WT 334 ± 83). Moreover, HFD administration impaired both glucose tolerance and insulin sensitivity in WT mice, which was ameliorated in LysM-Cre FthKO mice. In addition, energy expenditure, mRNA expression of thermogenic genes, and body temperature were higher in KO mice with HFD than WT mice with HFD. In vitro experiments showed that iron content was reduced, and LPS-induced TNF-α mRNA upregulation was inhibited in a macrophage cell line transfected with Fth siRNA.
Conclusions/interpretation
Deletion of macrophage H-ferritin suppresses the inflammatory response by reducing intracellular iron levels, resulting in the prevention of HFD-induced obesity and diabetes. The findings from this study highlight macrophage iron levels as a potential therapeutic target for obesity and diabetes.

This is a post-peer-review, pre-copyedit version of an article published in Diabetologia. The final authenticated version is available online at: https://doi.org/10.1007/s00125-020-05153-0.