Background:
Obesity is increasing in prevalence worldwide, and is associated with cardiovascular disease, diabetes and inflammation. Dietary modification and/or supplementation have been evaluated for obesity treatment. We hypothesized that: 1) iron chelators would activate adipocyte hypoxia-signalling, activating brown/beige fat, and decreasing weight; and 2) this would be ineffective in mice lacking hypoxia-inducible factor (HIF1a) in brown/beige fat.
Methods:
Mice with floxed HIF-1a alleles (FC) were crossed with UCP1-Cre mice to generate brown/beige-fat HIF1a-null (bfHIF) mice. All mice were fed high-fat diet (HFD, 45% energy from fat) for 10 weeks, and then fed chow, HFD, or HFD+iron chelator (30 mg/kg/day) for 6 weeks (n=24/group).
Results:
FC and bfHIF mice gained similar amounts of weight over the first 10 weeks (+7.8g vs. +7.7g, respectively, p=0.87). When switched to chow, FC and bfHIF mice lost equivalent amounts of weight (p=0.78). In the mice that continued on HFD, bfHIF mice tended to gain less weight than FC mice (+5.6g vs. +3.1g, p=0.13). Notably, in mice that were switched to HFD+iron chelator, bfHIF mice lost less weight than FC mice (-1.8g vs. -3.6g, p=0.07). In FC mice, iron chelator caused increased expression of thermogenic genes (Ucp1, Ppargc1a, Prdm16, Cidea) in adipose tissue. The inguinal fat mass of FC mice (containing beige adipocytes) was half that of bfHIF mice (263mg vs. 493mg, respectively, p=0.039). There was no difference in the masses of other organs.
Conclusions:
Iron chelator treatment causes weight loss in mice, but the underlying mechanisms are unknown. Our data suggest that HIF1a in brown/beige adipose tissue is required for iron chelator-induced weight loss. Moreover, absence of HIF1a in brown/beige adipocytes may also mitigate HFD-induced weight gain. Low-iron diets and iron chelators may be effective for the treatment or prevention of obesity, and this effect is at least partly mediated by HIF1a in brown/beige adipocytes.