DIETARY IRON OVERLOAD INDUCES VISCERAL ADIPOSE TISSUE INSULIN RESISTANCE ASSOCIATED WITH HYPER-RESISTINEMIA, AND SYNERGIZES WITH OBESITY IN INDUCING SYSTEMIC INSULIN RESISTANCE

Abstract Body
Background&Aims: Excess body iron is frequently observed in patients with metabolic syndrome (MetS), and associated with insulin resistance (IR) and organ damage. However, whether iron overload has a causal role in the pathophysiology of MetS is not well understood. Aim was to assess the effects of dietary modulation of iron status on IR and to investigate the underlying mechanisms in mouse models. Methods: Wild-type or ob/ob 4 week-old male C57BL/6 mice were fed for 16 weeks a standard iron concentration diet (8mg/kg, n=15) or an iron enriched diet (30g/kg:IED, n=15), with/without high-fructose diet (HFD). Results: IED was associated with increased serum/hepatic iron (comparable to that observed in patients with MetS). Despite IED reduced weight gain, due to reduced visceral adipose tissue mass (VAT; perigonadal fat pad:-60%, p=0.02), it induced a progressive increase in glucose due to IR, confirmed by i.p.insulin tolerance test. In ob/ob mice IED led to overt diabetes and in HFD fed mice increased IR by about 100%, associated with decreased VAT despite no changes in total body mass, thus suggesting VAT-IR. IED increased VAT-IR, as shown by decreased fasting pAKT/AKT ratio (-80%,p=0.03), and VAT iron accumulation with oxidative stress and UPR activation. In addition, IED induced increased VAT resistin mRNA levels (p=0.005), which resulted in hyper-resistinemia (p=0.01) and increased VAT expression of SOCS3 (p<0.05), a resistin target implicated in the pathogenesis of IR. Conclusions: IED induces IR in C57/BL6 mice and synergizes with obesity in the pathogenesis of metabolic complications.