DIETARY IRON OVERLOAD INDUCES VISCERAL ADIPOSE TISSUE INSULIN RESISTANCE: SYNERGY WITH OBESITY IN INDUCING SYSTEMIC INSULIN RESISTANCE

Background & Aims Excess body iron is frequently observed in patients with metabolic syndrome (MetS), and associated with insulin resistance (IR) and organ damage. Whether iron overload plays 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 (8 mg/kg, n=15) or an iron-enriched diet (30 g/kg –IED-, n=15), with or without high-fructose diet (HFD). Results IED was associated with increased serum/hepatic iron content (similarly to 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, as assessed 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%, decreased VAT despite no changes in total body mass, suggesting that VAT critically contributed to IR. IED increased VAT-related IR, as shown by decreased fasting pAKT/AKT ratio (-80%, p=0.03) and VAT iron accumulation with oxidative stress and UPR activation. IED also 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 C57BL/6 mice and synergizes with obesity in the pathogenesis of metabolic complications