The obesity epidemic is a significant global health crisis, and is closely associated with numerous metabolic disease processes such as type 2 diabetes. Hypoxia-inducible factors (HIFs) are transcription factors involved in regulating numerous cellular processes, including lipid and glucose metabolism. Iron regulates HIFs, with iron chelation increasing levels of HIF protein.
Aims and Methods:
C57Bl/6 mice were fed high fat diet (HFD) with or without addition of the iron chelator deferasirox (DFS) for 10 weeks. The effects of HFD±DFS on energy expenditure of subcutaneous fat were measured using the Seahorse Bioanalyser. Gene expression was measured in fat of the mice.
HDS+DFS mice had significantly lower weight gain, lighter subcutaneous and visceral fat depots, and better glucose tolerance compared to HFD mice. Histological examination of subcutaneous fat showed increased UCP-1 positive area in subcutaneous fat of HFD+DFS mice. There were 2-3 fold increases in expression of Pgc-1a, Prdm16 and Ucp-1 in the subcutaneous fat of the mice.
HFD+DFS mice had markedly higher oxygen consumption, and HFD+DFS subcutaneous fat explants had a 32 % increase in oxygen consumption rate measured by the Seahorse.
DFS ameliorated the subcutaneous and visceral fat gain and glucose intolerance caused by HFD. The beneficial metabolic outcome of DFS related to the upregulation of brown/ beige genes within subcutaneous white fat, inducing a ‘browning’ effect with resultant increased mitochondrial oxygen consumption and overall body energy expenditure. Thus, if well-tolerated in human subjects, iron chelators may be a novel therapy for the treatment of diet-induced obesity.