Overexpression of H Ferritin and Up-regulation of Iron Regulatory Protein Genes during Differentiation of 3T3-L1 Pre-adipocytes

Festa, Michela; Ricciardelli, Gaetano; Mele, Guido; Pietropaolo, C; Ruffo, A; Colonna, Alfredo

doi:10.1074/jbc.m004988200

Cited by 66 publications

(53 citation statements)

References 29 publications

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“…We previously demonstrated in differentiated 3T3-L1 adipocytes an accumulation of ferritin mRNA with a consequent increased content of H-rich isoferritin that may limit the toxicity of iron in adipose tissue, thus exerting an antioxidant function [35]. In the present study we found that the systemic iron deficiency in ovariectomized rats is linked to an opposite condition in adipose tissue, similar to that observed in iron-rich cells in which ferritin content enhanced and TfR-1 expression 14 decreased.…”

Section: Discussionsupporting

confidence: 87%

“…A number of studies have reported a correlation between obesity and poor iron status [33][34][35], although the molecular basis underlying this phenomenon is still obscure.…”

Section: Discussionmentioning

confidence: 99%

“…It has been previously reported a specific regulation of iron homeostasis, with a consistent accumulation of ferritin, in mature adipocytes [35].…”

Section: Introductionmentioning

confidence: 86%

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Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

Raso

Irace

Esposito

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 30A c c e p t e d M a n u s c r i p Graphical AbstractPage 2 of 30 A c c e p t e d M a n u s c r i p t E-mail address: rsantama@unina.it (R. Santamaria). * ManuscriptPage 3 of 30 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACTIron is essential for many biological processes and its deficiency or excess is involved in pathological conditions. At cellular level, the maintenance of iron homeostasis is largely accomplished by the transferrin receptor (TfR)-1 and by ferritin, whose expression is mainly regulated post-transcriptionally by Iron Regulatory Proteins (IRPs).This study examines the hypothesis that modification of serum estrogen levels by ovariectomy and 17β-estradiol (E 2 ) treatment in rats modulate serum iron-status parameters and iron metabolism in adipose tissue. In particular, we evaluated the RNA binding of IRP1 by electrophoretic mobility shift assay and IRP1, ferritin, and TfR-1 expression in adipose tissue by Western blot analysis.Ovariectomy, besides a lowered serum iron and transferrin iron binding capacity, remarkably decreased the binding activity of IRP1 in peritoneal and subcutaneous adipose tissues, and these effects were reversed by E 2 treatment. Moreover, ovariectomy determined a decrease of IRP1 expression, which was significant in subcutaneous adipose tissue. Consistent with IRP1 regulation, an increase of ferritin and a decrease of TfR-1 expression were observed in peritoneal adipose tissue from ovariectomized animals, while the treatment with E 2 reconstituted TfR-1 level. A similar expression profile of TfR-1 was observed in subcutaneous adipose tissue, where ferritin level did not change in ovariectomized animals, and was increased after E 2 treatment.Our results indicate that estrogen level changes can regulate the binding activity of the IRP1, and consequently ferritin and TfR-1 expression in adipose tissue, suggesting a relationship among serum and tissue iron parameters, estrogen status and adiposity.

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Section: Discussionsupporting

confidence: 87%

“…A number of studies have reported a correlation between obesity and poor iron status [33][34][35], although the molecular basis underlying this phenomenon is still obscure.…”

Section: Discussionmentioning

confidence: 99%

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Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

Raso

Irace

Esposito

et al. 2009

Biochemical Pharmacology

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“…Adipocytes accumulate fat during differentiation, and stored iron and the expression of several iron-related genes change at the same time (44).…”

Section: Iron Affects Adipocyte Differentiation and Adipose Tissue Hymentioning

confidence: 99%

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

2015

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OBJECTIVEThe bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. RESEARCH DESIGN AND METHODSThe mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing b-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). RESULTSThe mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate b-cells and insulin secretion, although this has been scarcely studied. CONCLUSIONSIron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted.Iron levels help to modulate the clinical manifestations of numerous systemic diseases. The importance of adequate amounts of iron for health and well-being in humans is well known. Iron is involved in binding and transporting oxygen and regulating cell growth and differentiation, as well as electron transport, DNA synthesis, and many important metabolic processes (1).From a clinical standpoint, assessing serum ferritin concentrations is a useful measure of iron storage. Ferritin is also an acute-phase reactant and, as such, is

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“…Circulating markers of iron overload are also positively associated with visceral and subcutaneous fat depots [9] and with adipocyte insulin resistance [10]. A previous study using the 3T3-L1 mouse cell line suggested the importance of iron-related genes in adipocyte physiology [11]. Interestingly, recent studies in mice revealed that an iron-enriched diet induced iron accumulation and insulin resistance in visceral adipose tissue (VAT) [12] and that adipocyte iron overload reduced adiponectin biosynthesis in parallel with induction of insulin resistance [13].…”

Section: Introductionmentioning

confidence: 99%

Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis

et al. 2014

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Aims/hypothesis Adipose tissue from obese and insulinresistant individuals showed altered expression of several iron-related genes in a recent study, suggesting that iron might have an important role in adipogenesis. To investigate this possible role, we aimed to characterise the effects of iron on adipocyte differentiation. Methods Intracellular iron deficiency was achieved using two independent approaches: deferoxamine administration (20 and 100 μmol/l) and transferrin knockdown (TF KD). The effects of added FeSO 4 , holo-transferrin and palmitate were studied during human and 3T3-L1 adipocyte differentiation. Finally, the relationship between iron-related and mitochondrialrelated genes was investigated in human adipose tissue. Results Most adipose tissue iron-related genes were predominantly expressed in adipocytes compared with stromal vascular cells. Of note, transferrin gene and protein expression increased significantly during adipocyte differentiation. Both deferoxamine and TF KD severely blunted adipocyte differentiation in parallel with increased inflammatory mRNAs. These effects were reversed in a dose-dependent manner after iron supplementation. Palmitate administration also led to a state of functional intracellular iron deficiency, with decreased Tf gene expression and iron uptake during adipocyte differentiation, which was reversed with transferrin co-treatment. On the other hand, iron in excess impaired differentiation, but this antiadipogenic effect was less pronounced than under iron chelation. Of interest, expression of several genes involved in mitochondrial biogenesis occurred in parallel with expression of iron-related genes both during adipogenesis and in human adipose tissue. Conclusions/interpretation Precise and fine-tuned iron availability is essential to achieve optimal adipocyte differentiation, possibly modulating adipocyte mitochondrial biogenesis.

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Overexpression of H Ferritin and Up-regulation of Iron Regulatory Protein Genes during Differentiation of 3T3-L1 Pre-adipocytes

Cited by 66 publications

References 29 publications

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis

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