Dietary Iron Overload Induces Visceral Adipose Tissue Insulin Resistance

Abstract

Increased iron stores associated with elevated levels of the iron hormone hepcidin are a frequent feature of the metabolic syndrome. The aim of this study was to assess the effect of dietary iron supplementation on insulin resistance and the role of hepcidin in C57Bl/6 male mice fed a standard or iron-enriched diet for 16 weeks. Iron supplementation increased hepatic iron and serum hepcidin fivefold and led to a 40% increase in fasting glucose due to insulin resistance, as confirmed by the insulin tolerance test, and to threefold higher levels of triglycerides. Iron supplemented mice had lower visceral adipose tissue mass estimated by epididymal fat pad, associated with iron accumulation in adipocytes. Decreased insulin signaling, evaluated by the phospho-Akt/Akt ratio, was detected in the visceral adipose tissue of iron overloaded mice, and gene expression analysis of visceral adipose tissue showed that an iron-enriched diet up-regulated iron-responsive genes and adipokines, favoring insulin resistance, whereas lipoprotein lipase was down-regulated. This resulted in hyperresistinemia and increased visceral adipose tissue expression of suppressor of cytokine signaling-3 (Socs3), a target of resistin and hepcidin implicated in insulin resistance. Acute hepcidin administration down-regulated lipoprotein lipase and up-regulated Socs3 in visceral adipose tissue. In conclusion, we characterized a model of dysmetabolic iron overload syndrome in which an iron-enriched diet induces insulin resistance and hypertriglyceridemia and affects visceral adipose tissue metabolism by a mechanism involving hepcidin up-regulation.

Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis

“…These results suggest that iron accumulates in adipose tissue in humans with increased body fatness and impaired insulin action [15], as previously demonstrated in mice [12][13][14].…”

“…A previous study using the 3T3-L1 mouse cell line suggested the importance of iron-related genes in adipocyte physiology [11]. Interestingly, recent studies in mice revealed that an iron-enriched diet induced iron accumulation and insulin resistance in visceral adipose tissue (VAT) [12] and that adipocyte iron overload reduced adiponectin biosynthesis in parallel with induction of insulin resistance [13]. Another recent study in mice showed impaired macrophage iron handling in the setting of obesity-associated adipose tissue dysfunction, which resulted in adipocyte iron uptake and overload [14].…”

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

“…This ironenriched diet was associated at the same time with visceral adipose tissue hyperplasia and hypertrophy (45). An iron-restricted diet led to the opposite results, with low amounts of circulating free fatty acids and triglycerides (46).…”

Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease

“…Altered adipose tissue biology and dysregulation of adipokine synthesis may promote liver injury by increased insulin resistance and also by other direct and indirect effects on hepatic and adipose tissue lipid metabolism 8. Studies in animals and tissue culture models have demonstrated an iron‐induced dysregulation of the synthesis of three adipokines with such roles, namely adiponectin, leptin, and resistin 9, 10, 11…”

“…More recently, it has been demonstrated that iron down‐regulates the appetite‐suppressing hormone leptin in mice fed a high iron diet through iron‐dependent activation of cyclic adenosine monophosphate responsive element‐binding protein 10. Two other adipokines, resistin and retinol binding protein‐4 (RBP‐4), have been associated with insulin resistance,8 and iron has been proposed as a regulator of serum concentrations of both these hormones 11, 12. Tumor necrosis factor α (TNFα) and interleukin‐6 (IL‐6) are cytokines secreted from adipose tissue as adipokines as well as from other tissues 8.…”