Abstract
Tightly regulated iron metabolism prevents oxidative stress. Hepcidin is a hormone that regulates iron flow in plasma; its production is induced by an iron overload and by inflammation. It inhibits iron entry into the circulation by blocking dietary absorption in the duodenum, the release of recycled iron from macrophages and the exit of stored iron from hepatocytes. Varied signals responding to iron stores, erythropoietic activity and host defense converge to regulate hepcidin production and thereby affect iron homeostasis. Although it is known that hepcidin increases when interleukin 6 (IL-6) increases, the relationship between hepcidin, dyslipidemia, insulin resistance (IR) and visceral adiposity index (VAI) in adolescents with obesity is unclear. In this cross-sectional study of 29 obese adolescents and 30 control subjects, we explored the difference of hepcidin, iron metabolism markers and IL-6 between obese and non-obese adolescents, and identified associations with inflammation, atherogenic dyslipidemia and IR. As compared to lean controls, obese participants showed 67% higher hepcidin: 14,070.8 ± 7213.5 vs. 8419.1 ± 4826.1 pg/mLc; 70% higher ferritin: 94.4 ± 82.4 vs. 55.1 ± 39.6 pg/mLa and 120% higher IL-6: 2.0 (1.1–4.9) vs. 0.9 (0.5–1.3) pg/mLd. Transferrin, soluble transferrin receptor and total body iron (as measured by sTFR/ferritin, log10 sTFR/ferritin ratio and sTFR/log ferritin ratios) were not different between the two cohorts. In the whole cohort, hepcidin correlated with VAI (r = 0.29a), sd-LDL (r = 0.31b), HOMA-IR (r = 0.29a) and IL-6 (r = 0.35c). In obese adolescents hepcidin correlated with TG (r = 0.47b), VLDL-C (r = 0.43b) and smaller LDL2 (r = 0.39a). Hepcidin elevation in adolescents with obesity is linked more to inflammation and metabolic alterations than to iron metabolism since the other markers of iron metabolism were not different between groups, except for ferritin. Studies addressing the long-term effects of higher hepcidin levels and their impact on subclinical anemia and iron status are warranted. a p < 0.05; b p < 0.01, c p < 0.001 d p < 0.0001.
Highlights
We have recently shown that even in the absence of metabolic syndrome (MetS), there is insulin resistance (IR)-associated dyslipidemia with increased levels of triglycerides (TGs), very-low-density lipoproteins (VLDLs) and small dense low-density lipoprotein, as well as early endothelial function alterations such as impaired flow-mediated dilation (FMD) in obese vs. lean adolescents [10]
All three ratios were not significantly different between obese and lean adolescents, which argues for an apparent dissociation between the higher hepcidin levels we found and iron status—that is, if the higher hepcidin levels were due only to iron status, we would have found evidence of iron overload that would justify it
Adolescents with obesity had 67% higher levels of hepcidin compared to their lean counterparts, which is in agreement with data from the literature [14,15,16]
Summary
Hepcidin is expressed mainly in the liver, studies indicate that it can be expressed in macrophages and adipose tissue under the conditions of inflammation [5,6] It is precisely when metabolic syndrome (MetS), which is a complex metabolic disorder, is present that the role of hepcidin as a regulator of iron overload may be subverted and become detrimental to iron balance. In all likelihood, elevated IL-6 in portal blood stimulates hepatic hepcidin synthesis when central obesity is present [7,8,9] In this case, a signal that should be physiologically protective to deprive bacteria from iron may become detrimental and affect iron metabolism.
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