Simulated microgravity decreases circulating iron in rats: role of inflammation‐induced hepcidin upregulation

Abstract

What is the central question of this study? Although microgravity is well known to reduce circulating iron in astronauts, the underlying mechanism is still unknown. We investigated whether hepcidin, a key hormone regulating iron metabolism, could be involved in this deleterious effect. What is the main finding and its importance? We show that hindlimb suspension, a model of microgravity, stimulates the production of hepcidin in liver of rats. In agreement with the biological role of hepcidin, we found a decrease of circulating iron and an increase of spleen iron content in hindlimb-unloaded rats. Consequently, our study supports the idea that hepcidin could play a role in the alteration of iron metabolism parameters observed during spaceflight. During spaceflight, humans exposed to microgravity exhibit an increase of iron storage and a reduction of circulating iron. Such perturbations could promote oxidative stress and anaemia in astronauts. The mechanism by which microgravity modulates iron metabolism is still unknown. Herein, we hypothesized that microgravity upregulates hepcidin, a hormone produced by the liver that is the main controller of iron homeostasis. To test this hypothesis, rats were submitted to hindlimb unloading (HU), the reference model to mimic the effects of microgravity in rodents. After 7 days, the mRNA level of hepcidin was increased in the liver of HU rats (+74%, P = 0.001). In agreement with the biological role of hepcidin, we found an increase of spleen iron content (+78%, P = 0.030) and a decrease of serum iron concentration (-35%, P = 0.002) and transferrin saturation (-25%, P = 0.011) in HU rats. These findings support a role of hepcidin in microgravity-induced iron metabolism alteration. Furthermore, among the signalling pathways inducing hepcidin mRNA expression, we found that only the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) axis was activated by HU, as shown by the increase of phospho-STAT3 (+193%, P < 0.001) and of the hepatic mRNA level of haptoglobin (+167%, P < 0.001), a STAT3-inducible gene, in HU rats. Taken together, these data support the idea that microgravity may alter iron metabolism through an inflammatory process upregulating hepcidin.

Effects of Iron Overload and Oxidative Damage on the Musculoskeletal System in the Space Environment: Data from Spaceflights and Ground-Based Simulation Models

“…Iron deposition in the liver and spleen was significantly increased in mice after unloading for 28 days [ 18 , 44 ]. An increase of the spleen iron content also was found in a study of 7-day HLU rats [ 45 ]. Systemic iron metabolism is mainly controlled by hepcidin, a hormone produced by the liver.…”

“…Under inflammatory conditions, interleukin-6 (IL-6) and relevant cytokines bind to the IL-6 receptor, leading to the activation of signal transducer and activator of transcription 3 (STAT3), which in turn promotes hepcidin production [ 6 ]. After HLU for seven days, the mRNA levels of hepcidin were enhanced in the liver of rats, accompanied by the activation of the IL-6/STAT3 axis [ 45 ]. Therefore, these data imply that the changes in iron metabolism may be mediated through upregulating hepcidin via an inflammatory process in microgravity.…”

Simulated microgravity disturbs iron metabolism and distribution in humans: Lessons from dry immersion, an innovative ground‐based human model

“…8 Interestingly, hepatic hepcidin expression and blood hepcidin levels increase in rodents exposed to simulated microgravity. [8][9][10] As hepcidin controls iron release from cells, especially spleen macrophages, it could play a key role in microgravity-induced iron misdistribution by limiting the expression and activity of ferroportin, the cell iron exporter that allows iron recycling from macrophages in plasma. 11 Notably, it has been suggested that iron metabolism has strong interactions with other essential metals, especially due to the fact that some iron proteins could also participate in the metabolism of other metals.…”

Disorder of Iron Metabolism Inhibits the Recovery of Unloading-Induced Bone Loss in Hypomagnetic Field

“…On the ground, mechanical unloading‐induced bone loss in mice was connected with iron overload . In rats, a decrease in the levels of circulating iron and an increase in iron content of the spleen was found after unloading for 14 days . Interestingly, we have found that HyMF aggravated the increase of body iron storage induced by HLU in mice .…”