Iron chelation increases beige fat differentiation and metabolic activity, preventing and treating obesity

Abstract

Beige and brown fat consume glucose and lipids to produce heat, using uncoupling protein 1 (UCP1). It is thought that full activation of brown adipose tissue (BAT) may increase total daily energy expenditure by 20%. Humans normally have more beige and potentially beige-able fat than brown fat. Strategies to increase beige fat differentiation and activation may be useful for the treatment of obesity and diabetes. Mice were fed chow or high-fat diet (HFD) with or without the iron chelator deferasirox. Animals fed HFD + deferasirox were markedly lighter than their HFD controls with increased energy expenditure (12% increase over 24 h, p < 0.001). Inguinal fat from HFD + deferasirox mice showed increased beige fat quantity with greater Ucp1 and Prdm16 expression. Inguinal adipose tissue explants were studied in a Seahorse bioanalyser and energy expenditure was significantly increased. Deferasirox was also effective in established obesity and in ob/ob mice, indicating that intact leptin signalling is not needed for efficacy. These studies identify iron chelation as a strategy to preferentially activate beige fat. Whether activating brown/beige fat is effective in humans is unproven. However, depleting iron to low-normal levels is a potential therapeutic strategy to improve obesity and related metabolic disorders, and human studies may be warranted.

Mitochondrial Energy Metabolism in the Regulation of Thermogenic Brown Fats and Human Metabolic Diseases

“…Ferritin is the major iron storage protein complex, and the serum levels of ferritin are used to estimate body iron storage level, which is associated with the development of insulin resistance and metabolic syndrome [ 230 , 231 ]. In agreement, a recent report indicated that mice fed with an HFD and an iron chelator deferasirox exhibited protective effects against diet-induced obesity along with elevated energy expenditure and beige adipogenesis in WAT [ 232 ]. Genetic and pharmacological inhibition of these iron metabolic pathways in mitochondria induced obesity along with decreased energy expenditure [ 233 ].…”

Phenylhydrazine‐induced anaemia reduces subcutaneous white and brown adipose tissues in hypothalamic obese rats

“…Taken together, our data point to an anti‐adiposity effect of PHZ in hypothalamic obese animals, corroborating recently published data showing that iron chelation increases beige fat differentiation and prevents obesity (Nazari et al., 2022). Interestingly, a reduction in visceral WAT depots was not observed in MSG PHZ rats, suggesting that this lipolytic action is limited to BAT and subcutaneous WAT.…”

“…showing that iron chelation increases beige fat differentiation and prevents obesity (Nazari et al, 2022). Interestingly, a reduction in visceral WAT depots was not observed in MSG PHZ rats, suggesting that this lipolytic action is limited to BAT and subcutaneous WAT.…”

“…Treatment of ID usually improves obesity and metabolic parameters (Tussing‐Humphreys et al., 2012). Interestingly, recent data suggest that iron is able to modulate the WAT and brown adipose tissue (BAT) by playing an anti‐adiposity role (Nazari et al., 2022). Moreover, erythropoietin (Epo), an essential hormone for effective erythropoiesis, regulates WAT mass and inflammation (Suresh et al., 2020).…”

Emerging Roles of the Iron Chelators in Inflammation

“…Recently, Nazari et al confirmed the effects of iron chelators on adipose tissue, demonstrating that DFX is able to activate beige fat differentiation and metabolic activity, thus suggesting it as a potential therapeutic strategy to treat obesity and to prevent its metabolic complications. Interestingly, in C57Bl/6 mice, placed on high-fat diet and treated or not with DFX, they analyzed the inguinal fat, a classically brown or beige fat store in mice, observing an increase in UCP1 positive cells after DFX administration [ 94 ].…”