Iron chelation for treating obesity and components of the metabolic syndrome

Epidemiological studies suggest a link between iron stores and components of the metabolic syndrome. Human subjects with ironoverload syndromes are more prone to obesity, diabetes and metabolic syndrome. Excess iron can generate Reactive Oxygen Species(ROS) resulting in insulin resistance and cell apoptosis. Iron chelation reduces diabetes in iron overload syndromes but effects onobesity and related metabolic variables are unknown in non-overloaded individuals. Hypoxia Inducible Factor- 1-alpha (HIF-1α) is atranscription factor up-regulated by hypoxia, which is also increased by iron chelation in-vitro. HIF-1α impacts lipid and whole bodymetabolism and cellular survival by improving glucose uptake, facilitating anaerobic glycolysis, and attenuating ROS.Hypothesis: That iron chelation may treat or prevent components of the metabolic syndrome via HIF-1 induction. This thesisinvestigated effects of iron chelators on murine models of obesity and diabetes: C57Bl/6 mice on high fat diet (HFD), ob/ob mice onchow diet, C57Bl/6 mice on chow, and Non-Obese Diabetic (NOD) mice. Two iron chelators were studied: Deferoxamine (DFO) as anintra-peritoneal injection weekly and continuous oral Deferasirox (DFS) mixed with diet. DFS-treatment had important metabolicbenefits, including reduction of weight gain in both male and female mice, from as early as 1 week, lasting throughout the period ofstudy (up to 9 months). Other benefits included lower plasma lipids, reduction of hepatic steatosis and improvement in insulinresistance. There was also improved beta cell function, evidenced by relatively preserved first phase insulin secretion and improvedglucose tolerance, particularly after prolonged high fat exposure. DFS treatment reduced hepatic iron and increased HIF-1α, associatedwith down-regulation of hepatic lipogene expression and improved insulin signalling gene expression. Importantly, DFS did not impairappetite and had no apparent toxicity. Treated mice gained weight as per normal chow-fed C57Bl/6 mice and were not renderedanaemic. Rather than reducing appetite, DFS appeared to increase appetite. This, together with increased core body temperature,suggested improved whole body metabolism. Metabolic chamber studies confirmed this, showing higher O2 consumption and CO2production in DFS-treated mice. These findings suggest iron chelation may be effective in improving the metabolic derangementsassociated with obesity