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Progressive Increases in Dietary Iron Are Associated with the Emergence of Pathologic Disturbances of Copper Homeostasis in Growing Rats.

ABSTRACT: Background:Consumption of a high-iron diet causes copper deficiency in weanling rodents; however, the minimum amount of dietary iron that disrupts copper homeostasis has not been established. Objective:We tested the hypothesis that dietary iron at only several-fold above physiologic requirements would cause copper depletion. Methods:Weanling male Sprague-Dawley rats (n = 6/group) were fed AIN-93G-based diets with adequate (88 µg Fe/g = 1×), or excessive (4×, 9.5×, 18.5×, 38×, or 110×) iron content for 7 wk (110× group, due to notable morbidity) or 8 wk (all other groups). Copper-related physiologic parameters were then assessed. Results:A hierarchy of copper-related, pathologic symptoms was noted as dietary iron concentrations increased. All statistical comparisons reported here refer to differences from the 1× (i.e., control) group. The highest iron concentration (110×) impaired growth (final body weights decreased ∼40%; P < 0.0001), and caused anemia (blood hemoglobin and hematocrit decreased ∼65%; P < 0.0001) and hepatic copper depletion (>85% reduction; P < 0.01). Cardiac hypertrophy occurred in the 110× (∼130% increase in mass; P < 0.0001) and 38× (∼25% increase; P < 0.05) groups, whereas cardiac copper content was lower in the 110× (P < 0.01), 38× (P < 0.01), and 18.5× (P < 0.05) groups (∼70% reductions). Splenic copper was also depleted in the 110× (>90% reduction; P < 0.0001), and in the 38× (P < 0.001) and 18.5× (P < 0.01) groups (∼70% reductions). Moreover, serum ceruloplasmin activity was decreased in the 110× and 38× (>90% reductions; P < 0.0001), and 18.5× (P < 0.001) and 9.5× (P < 0.05) (∼50% reductions) groups, typifying moderate to severe copper deficiency. Conclusions:Increasing dietary iron intakes to ∼9.5-fold above dietary recommendations caused copper deficiency. Importantly, human iron supplementation is common, and recommended intakes for at-risk individuals may be ≤10-fold above the RDA. Whether these iron intakes perturb copper metabolism is worth considering, especially since copper defi-ciency can impair iron utilization (e.g., by decreasing the ferroxidase activity of ceruloplasmin).

SUBMITTER: Ha JH

PROVIDER: S-EPMC6669950 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAdaptive thermogenesis is an iron-demanding pathway, significantly contributing to whole-body energy expenditure. However, the effects of iron-deficient diets on adaptive thermogenesis and obesity remain unknown.ObjectivesWe aimed to determine the impact of dietary iron deficiency on iron homeostasis in adipocytes, adaptive thermogenic capacity, and metabolic consequences in obesity.MethodsC57BL/6 male mice were assigned to either the iron-adequate (IA, 35 ppm) or the iron-deficient group (ID, 3 ppm) at weaning. Upon 8 wk of age, both IA and ID groups received an isocaloric high-fat diet (45% kcal from fat) for 10 wk, maintaining the same iron content. Mice (n = 8) were used to determine the iron status at the systemic and tissue levels and lipid metabolism and inflammatory signaling in adipose tissue. The same mice were used to evaluate cold tolerance (4°C) for 3 h. For assessing adaptive thermogenesis, mice (n = 5) received an intraperitoneal injection of β3-adrenoceptor agonist CL316243 (CL) for 5 d.ResultsCompared with the IA group, the ID group had nonanemic iron deficiency, lower serum ferritin (42.8%, P < 0.01), and greater weight gain (8.67%, P < 0.05) and insulin resistance (159%, P < 0.01), partly due to reduced AMP-activated protein kinase activation (61.0%, P < 0.05). Upon cold exposure, the ID group maintained a core body temperature 2°C lower than the IA group. The ID group had lower iron content (47.0%, P < 0.01) in the inguinal adipose tissue (iWAT) than the IA group, which was associated with impaired adaptive thermogenesis. In response to CL, ID mice showed decreased heat production (P < 0.01) and defective upregulation of beige adipocyte-specific markers, including uncoupling protein 1 (41.1%, P < 0.001), transferrin receptor 1 (47.5%, P < 0.001), and mitochondrial respiratory chain complexes (P < 0.05) compared with IA mice.ConclusionsDietary iron deficiency deregulates iron balance in the iWAT and impairs adaptive thermogenesis, thereby escalating the diet-induced weight gain in C57BL/6 mice.

Project description:The transition metal copper (Cu) is an essential element for all living organisms. In plants, Cu plays key roles in electron transport chains of chloroplasts and mitochondria, as well as in cell wall metabolism, ethylene perception, molybdenum cofactor synthesis and oxidative stress protection. Because of its physiological importance, suboptimal concentrations of Cu trigger a re-organization of metabolism to economize on Cu, and pronounced Cu deficiency causes severe growth reduction and defects in male fertility. However, when present in excess, Cu can be highly toxic. Therefore, Cu uptake, utilization and cellular concentrations are strictly regulated. A number of components of the Cu-homeostatic network of Arabidopsis have already been identified. However, the mechanisms that control responses of plant gene expression to Cu-deficiency are only partly understood. In Chlamydomonas reinhardtii, the transcription factor Crr1 is required for activating and/or repressing the expression of a number of genes in response to Cu deficiency. This protein contains a plant-specific DNA-binding domain (SBP domain), ankyrin repeats and a C-terminal cysteine-rich region with similarity to a Drosophila metallothionein (MT). In Arabidopsis, there is a family of 16 proteins with SBP domains named SPL family (SBP-like) of which a subset of proteins have been implicated in flowering time control and floral development. Among all of them, AtSPL7 is the most similar to Crr1 (27 % identity), and AtSPL1 (25 % identity), AtSPL12 (24 % identity) and AtSPL14 (23 % identity) share a common protein architecture. The goal of this work was to obtain a complete account of the response of the Arabidopsis thaliana transcriptome to Cu deficiency, as well as to determine the role of AtSPL7 in the transcriptional response to Cu deficiency. For this purpose, three independent experiments were carried out including Col-0 wild-type and spl7-2 mutant plants grown in Cu-sufficient and Cu-deficient hydroponic media, respectively. Root and shoot transcriptomes were established by RNA-Seq for quantitative comparisons. Sampling of root and shoot tissues of wild-type (WT, Col-0) and spl7-2 mutant plants (the mutant is knock-down for the transcription factor SPL7, which plays a key role in the transcriptional regulation of the copper deficiency responses) cultivated hydroponically in a modified Hoagland's solution under Cu-sufficient (control) and Cu-deficient conditions.

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Progressive Increases in Dietary Iron Are Associated with the Emergence of Pathologic Disturbances of Copper Homeostasis in Growing Rats.

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