Iron Chelation Prevents Obesity by Increasing Hypothalamic Hypoxia-Inducible Factor-1α, Metabolic Rate and Adipose Tissue Browning (#37)
Background: Increased body iron status has been linked to an increased risk of obesity, metabolic syndrome and diabetes. In contrast, lower iron status associates with a decreased risk of obesity and associated diseases. In animal studies, iron deficient diets improved diabetes. Although a mechanistic link between high iron levels and metabolic activity is yet to be identified, one possibility is the regulation of the transcription factors Hypoxia Inducible Factors 1α (HIF-1α) and 2α (HIF-2α), both of which are known to be stabilised by iron depletion. We examined the effects of decreasing body iron stores upon development of obesity in mice.
Methods: Mice were fed a high-fat diet (HFD) with or without the oral iron chelator deferasirox (DFS). We have previously shown that DFS can increase HIF-1α protein levels both in vitro and in vivo (Cheng et al., JCI, 2010).
Results: Iron chelation completely prevented excess weight gain in mice on a HFD, without rendering mice anemic. HFD+DFS fed mice ate slightly more, had increased metabolic rate and body temperature. In addition, DFS treatment led to a 3-6 fold increase in ‘browning’ of white adipose tissue and increased expression of genes involved in brown fat programming, including Prdm16, Ppargc1a (encoding PGC1α) and Ucp1. The hypothalamus regulates food intake, weight and energy expenditure. To investigate whether the effects of DFS were centrally mediated, hypothalamic arcuate nucleus specific HIF-1α-null mice were created. These mice were resistant to the beneficial effects of DFS on weight and white adipose tissue ‘browning’.
Discussion: Our data demonstrate that 1) iron chelation prevents obesity in mice on a HFD by increasing energy expenditure, 2) iron chelation induces white adipose tissue ‘browning’ and 3) hypothalamic HIF-1α is a novel and important regulator of weight and energy expenditure. This is a potential new therapeutic strategy for treatment of human obesity.