High rates of fatty acid (FA) mobilization from adipose tissue are associated with insulin resistance (IR) in obesity. In vitro evidence suggests that iron stimulates lipolysis in adipocytes, but whether iron is related to in vivo FA mobilization is unknown. We hypothesized that plasma ferritin concentration ([ferritin]), a marker of body iron stores, would be positively associated with FA mobilization. We measured [ferritin], the rate of appearance of FA in the systemic circulation (FA Ra; stable isotope dilution), key adipose tissue lipolytic proteins and IR (hyperinsulinaemic-euglycaemic clamp) in 20 obese, premenopausal women. [Ferritin] was correlated with FA Ra (r = 0.65; P = 0.002) and IR (r = 0.57; P = 0.008); these relationships remained significant after controlling for body mass index and plasma [C-reactive protein] (a marker of systemic inflammation) in multiple regression analyses. We then stratified subjects into tertiles based on [ferritin] to compare subjects with 'High-ferritin' versus 'Low-ferritin'. Plasma [hepcidin] was more than fivefold greater (P < 0.05) in the High-ferritin versus Low-ferritin group, but there was no difference in plasma [C-reactive protein] between groups, indicating that the large difference in plasma [ferritin] reflects a difference in iron stores, not systemic inflammation. We found that FA Ra, adipose protein abundance of hormone-sensitive lipase and adipose triglyceride lipase, and IR were significantly greater in subjects with High-ferritin versus Low-ferritin (all P < 0.05). These data provide the first evidence linking iron and in vivo FA mobilization and suggest that elevated iron stores might contribute to IR in obesity by increasing systemic FA availability.

New Findings What is the central question of this study?Obesity is associated with complex perturbations to iron homeostasis: is plasma ferritin concentration (a biomarker of whole‐body iron stores) related to the abundance of ferritin (the key tissue iron storage protein) in skeletal muscle in adults with obesity? What is the main finding and its importance?Plasma ferritin concentration was tightly correlated with the abundance of ferritin in skeletal muscle, and this relationship persisted when accounting for sex, age, body mass index and plasma C‐reactive protein concentration. Our findings suggest that skeletal muscle may be an important iron store. Abstract Obesity is associated with complex perturbations to whole‐body and tissue iron homeostasis. Recent evidence suggests a potentially important influence of iron storage in skeletal muscle on whole‐body iron homeostasis, but this association is not clearly resolved. The primary aim of this study was to assess the relationship between whole‐body and skeletal muscle iron stores by measuring the abundance of the key iron storage (ferritin) and import (transferrin receptor) proteins in skeletal muscle, as well as markers of whole‐body iron homeostasis in men (n = 19) and women (n = 43) with obesity. Plasma ferritin concentration (a marker of whole‐body iron stores) was highly correlated with muscle ferritin abundance (r = 0.77, P = 2 × 10−13) and negatively associated with muscle transferrin receptor abundance (r = −0.76, P = 1 × 10−12). These relationships persisted when accounting for sex, age, BMI and plasma C‐reactive protein concentration. In parallel with higher whole‐body iron stores in our male versus female participants, men had 2.2‐fold higher muscle ferritin abundance (P = 1 × 10−4) compared with women. In accordance with lower muscle iron storage, women had 2.7‐fold higher transferrin receptor abundance (P = 7 × 10−10) compared with men. We conclude that muscle iron storage and import proteins are tightly and independently related to plasma ferritin concentration in adults with obesity, suggesting that skeletal muscle may be an underappreciated iron store.

The regulation of iron storage is crucial to human health, because both excess and deficient iron storage have adverse consequences. Recent studies suggest altered iron storage in adults with obesity, with increased iron accumulation in their liver and skeletal muscle. Exercise training increases iron use for processes such as red blood cell production and can lower whole-body iron stores in humans. However, the effects of exercise training on liver and muscle iron stores in adults with obesity have not been assessed. The aim of this study was to determine the effects of 12 weeks of exercise training on whole-body iron stores, liver iron content and the abundance of ferritin (the key iron storage protein) in skeletal muscle in adults with obesity. Twenty-two inactive adults (11 women and 11 men; age, 31 ± 6 years; body mass index, 33 ± 3 kg/m 2) completed 12 weeks (four sessions/week) of either moderate-intensity continuous training (MICT; 45 min at 70% of maximal heart rate; n = 11) or high-intensity interval training (HIIT; 10 × 1 min at 90% of maximal heart rate, interspersed with 1 min active recovery; n = 11). Whole-body iron stores were lower after training, as indicated by decreased plasma concentrations of ferritin (P = 3 × 10 −5) and hepcidin (P = 0.02), without any change in C-reactive protein. Hepatic R2*, an index of liver iron content, was 6% lower after training (P = 0.06). Training reduced the skeletal muscle abundance of ferritin by 10% (P = 0.03), suggesting lower muscle iron storage. Interestingly, these adaptations were similar in MICT and HIIT groups. Our findings indicate that exercise training decreased iron storage in adults with obesity, which might have important implications for obese individuals with dysregulated iron homeostasis. K E Y W O R D S exercise training adaptations, iron homeostasis, iron storage 1 INTRODUCTION Iron is an essential micronutrient that must be regulated precisely at the systemic and tissue levels. Inadequate iron bioavailability can lead to the development of iron deficiency anaemia but, because