The Role of Iron-Chelation and Hypoxia-Inducible Factor 1α in Metabolism and Obesity

Abstract

Adipose tissue has an essential role in the regulation of systemic energy balance. Mammals have two types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT). BAT is a specialized to produce heat and protect the body against hypothermia and obesity through non-shivering thermogenesis. BAT can also profoundly affect body weight and glucose metabolism in animal models. Iron plays an important role in oxidative stress and free radical pathology. In this study the effects of an oral iron chelator deferasirox (DFS) were examined. The findings showed mice fed high fat diet (HFD) with DFS exhibited an increase in metabolic rate which prevented high fat diet-induced obesity. Deferasirox showed positive impacts on glucose metabolism, insulin resistance, and energy expenditure at 16 weeks. Increase in pro-thermogenic genes and reduction in classic white adipose tissue mRNAs were associated with higher oxygen consumption rate and energy expenditure. In obesity, hyperplasia and hypertrophy of adipocytes can result in relative hypoxia in white and brown adipose tissues. This study also investigated the role of hypoxia inducible factor 1α (Hif1α) in brown/beige adipocytes. Transgenic mice with floxed Hif1α alleles (FC) were bred with UCP1-Cre mice to generate brown/beige-fat Hif1α-null (bfhif). In this study bfhif mice fed HFD were resistant to HFD-induced obesity. Consistent with body weight results, bfhif mice revealed lower fat mass and body fat percentage, with higher basal oxygen consumption rate. The novelty of this study is that results have shown that deletion of Hif1α in brown / beige adipocytes improved HFD-induced obesity, glucose tolerance and mitochondrial respiration. Therefore both iron chelation, and the therapeutic deletion of Hif1α in brown / beige adipocytes are potential therapies for preventing or treating obesity and related metabolic disorders.