Objectives : Iron deficiency anemia (IDA) is a common disease related to malnutrition. Epidemiological studies revealed a positive correlation between IDA and obesity, but the underlying mechanism is uncertain. Emerging evidence suggests that adipose browning significantly contributes to weight loss by dissipating extra energy into heat. Adipose tissue browning is concurrent with mitochondrial biogenesis, an iron-demanding process. We aimed to investigate whether iron deficiency downregulat adipose tissue browning.
Methods : To simulate the IDA, C57BL/6 mice were fed a high-fat diet in an iron-deficient (3ppm) setting for 14 weeks compared with an isocaloric iron-sufficient (50ppm) diet. Iron status was evaluated by measuring serum levels of ferritin, hemoglobin (Hb) and hematocrit (HCt). Iron content of tissue levels was measured by ICP-Mass spectrometer. For assessment of capability to keep the temperature homeostasis, core body temperature and heat release by the infrared camera were determined upon acute cold exposure (4◦C). Adipose browning was induced by administrating β3-adrenoceptor agonist, CL316243 (CL) for 5 days. The significance of iron on adipocyte browning was validated in vitro by silencing of the transferrin receptor (TfR), or by iron chelator (DFO, deferoxamine) treatment during beige adipogenesis.
Results : The chronic iron-deficiency significantly reduced serum ferritin concentration (p< 0.01) with marginal impact on Hb or HCt. Despite no apparent difference in body weight, fat mass was higher in IDA mice (p< 0.001). Consistently, total iron content in the inguinal fat, where adipose browning occurs, was markedly lower in IDA mice. IDA mice were more susceptible to cold treatment, maintaining the body temperature lower than control and defective in heat release. Upon CL stimulation, IDA mice showed reduced expression of uncoupling protein 1 (UCP1) and Cytc, and beige-like morphology in the inguinal fat. Supporting these in vivo results, inhibition of iron import by depleting TfR or reducing liable iron dampened the beige adipogenesis by attenuating brown-specific markers and mitochondrial biogenesis.
Conclusions : IDA is an independent risk factor for visceral obesity by decreasing thermogenic energy expenditure.
Funding Sources : National Institutes of Health Grant 1R21HD094273