Ablation of hephaestin and ceruloplasmin results in iron accumulation in adipocytes and type 2 diabetes

Abstract

Little is known about the iron efflux mechanism in adipocytes. Here, we used hephaestin (Heph) and ceruloplasmin (Cp) single-knockout (KO) mice and Heph/Cp double-KO mice to investigate the roles of multicopper ferroxidases (MCFs) in this process. We show that both HEPH and CP are expressed in subcutaneous adipose tissue. Ablation of either MCF leads to a compensatory increase in the other, which contributes to the balance of iron status. However, ablation of both MCFs together induces severe iron deposition in adipocytes which is associated with decreased adiponectin and leptin mRNA expression. Furthermore, Heph/Cp KO mice display disordered carbohydrate metabolism characterized as type 2 diabetes. Together, these results demonstrate the protective roles of HEPH and CP in preventing iron overload in adipocytes.

Regulation of tissue iron homeostasis: the macrophage “ferrostat”

“…Regulated control of local iron homeostasis is important in AT for two major reasons: (i) iron availability is necessary for normal adipogenesis (121); and (ii) excess fatty acids in adipocytes, particularly in the context of obesity, react with free iron and induce lipid peroxidation chain reactions, leading to aberrant oxidative stress (122). Along these lines, previous evidence shows that iron overload in adipocytes attenuates systemic insulin sensitivity via what appears to be an adiponectin-dependent mechanism (121,123). Similarly, Gabrielsen et al reported that adipocyte-targeted deletion of Fpn using the aP2-Cre mouse model triggers insulin resistance (121).…”

Ceruloplasmin and hephaestin jointly protect the exocrine pancreas against oxidative damage by facilitating iron efflux

“…However, recent studies have shown that HEPH and CP are co-expressed in many tissues (e.g. kidney, adipose tissue, brain) [19] , [23] , [24] , [25] . Ablation of HEPH and CP globally induces significant iron accumulation in these tissues, and leads to dramatically lower plasma iron and anemia [19] , [23] , [24] , [25] .…”

“…kidney, adipose tissue, brain) [19] , [23] , [24] , [25] . Ablation of HEPH and CP globally induces significant iron accumulation in these tissues, and leads to dramatically lower plasma iron and anemia [19] , [23] , [24] , [25] . Our recent work has demonstrated the mutually compensatory roles of HEPH and CP in adipose tissue, and how loss of both MCFs results in adipocyte iron deposition, insulin resistance and type 2 diabetes [24] .…”

“…Ablation of HEPH and CP globally induces significant iron accumulation in these tissues, and leads to dramatically lower plasma iron and anemia [19] , [23] , [24] , [25] . Our recent work has demonstrated the mutually compensatory roles of HEPH and CP in adipose tissue, and how loss of both MCFs results in adipocyte iron deposition, insulin resistance and type 2 diabetes [24] . Notably, Heph/Cp KO mice display a significantly increased plasma insulin level, indicating that the insulin secretion was not impaired [24] .…”

The specific activity of proteins involved in iron metabolism depends on compensation of type 2 diabetes mellitus

“…Aceruloplasminemia being the result of a mutation in ceruloplasmin (Cp) gene is also associated with T2D. Recently double knockout of Cp and its homologue hephaestin (Hp) genes was demonstrated to cause T2D symptoms in mice [3].…”