Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus

Tran, Phu V.; Fretham, Stephanie J. B.; Wobken, Jane D.; Miller, Bradley S.; Georgieff, Michael

doi:10.1152/ajpendo.00369.2011

Cited by 47 publications

(33 citation statements)

References 72 publications

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“…The relationship of haematology and serum chemistry indicators to IGF-I status was extensively studied in humans and laboratory rodents, and a close interaction between iron and IGF-I was reported by Choi and Kim (2004) and by Tran et al (2012). In female adolescents, it is well established that serum IGF-I concentrations decrease gradually as body iron status falls (Choi and Kim 2004).…”

Section: Discussionmentioning

confidence: 92%

“…Although the positive correlation provides no indication of cause and effect, we consider that sufficient iron is required for normal secretion of IGF-I. Indeed, in situations of iron deficiency in rats, iron is a critical determinant of IGF-I regulation (Tran et al 2012), and previous research has also shown that iron deficiency reduces GH-mediated IGF-I secretion (Ceppi and Blum 1994). Nevertheless, conversely to what was observed in the iron deficiency state, parenteral administration of iron in calves during the early postnatal period resulted in a rise of serum IGF-I concentrations (Moosavian et al 2010).…”

Section: Indicatorsmentioning

confidence: 90%

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Relationship between serum iron and insulin-like growth factor-I concentrations in 10-day-old calves

et al. 2014

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Newborn calves are often deficient in iron and progressive reduction in blood iron concentration occurs over the first weeks of life. Some reports indicate the importance of interactions among iron and components of the insulin-like growth factor system. The aim of the study was to determine if there is a relationship between serum iron and insulin-like growth factor-I concentrations in neonatal calves. Blood samples were collected from 16 female Holstein-Friesian calves on day 10 of age. Erythrogram determination and measurements of serum iron, total protein, albumin, total iron binding capacity and serum insulin-like growth factor-I concentrations were performed. Haematological values were measured using an automatic analyzer, biochemical properties were determined spectrophotometrically, insulin-like growth factor-I concentration was measured by radioimmunoassay. Calves were divided into 2 groups according to iron concentrations; the first group of iron-deficient calves (n = 8, Fe < 10 μmol/l) and the second group of calves with optimal iron concentration (n = 8, Fe > 18 μmol/l). Blood indicators in all calves from the first group followed a pattern typically observed in anaemic calves. Insulin-like growth factor-I concentrations were significantly (P < 0.01) lower in the first group compared to the second group. However, insulin-like growth factor-I very strongly correlated with iron in calves from the second group compared to iron-deficient calves (r = 0.624; P < 0.01 and r = 0.478; P > 0.05, respectively). Based on our results, iron seems to have an important relationship to secretion of insulin-like growth factor-I in 10-day-old calves. This is the first report about such relationship in this age group of animals. Calf, haematology, IGF-I, iron deficiency

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Section: Discussionmentioning

confidence: 92%

Section: Indicatorsmentioning

confidence: 90%

Relationship between serum iron and insulin-like growth factor-I concentrations in 10-day-old calves

et al. 2014

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“…On the other hand, a number of proteins that are perturbed in the acutely ID hippocampus are no longer different from IS control at P65 and thus provide evidence for recovered pathways following iron treatment and repletion in our model. The unaltered signaling pathways include Cxcr4/RhoA, IGF1, thyroid hormone receptor, and HIF1a (data not shown), all of which are altered during the period of iron deficiency (2,7,70).…”

Section: Discussionmentioning

confidence: 94%

“…These proteins are known to play critical role in mediating learning and memory in the rat hippocampus. Analyses were performed using a previously described protocol (70). In brief, 30 g hippocampal protein lysate or 10 g synaptosomal fraction were separated using a 4 -20% SDS-PAGE gel (Novex, Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

Fetal iron deficiency alters the proteome of adult rat hippocampal synaptosomes

Tran

Dakoji

Reise

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Fetal and neonatal iron deficiency results in cognitive impairments in adulthood despite prompt postnatal iron replenishment. To systematically determine whether abnormal expression and localization of proteins that regulate adult synaptic efficacy are involved, we used a quantitative proteomic approach (isobaric tags for relative and absolute quantitation, iTRAQ) and pathway analysis to identify dysregulated proteins in hippocampal synapses of fetal iron deficiency model. Rat pups were made iron deficient (ID) from gestational day 2 through postnatal day (P) 7 by providing pregnant and nursing dams an ID diet (4 ppm Fe) after which they were rescued with an iron-sufficient diet (200 ppm Fe). This paradigm resulted in a 40% loss of brain iron at P15 with complete recovery by P56. Synaptosomes were prepared from hippocampi of the formerly iron-deficient (FID) and always iron-sufficient controls rats at P65 using a sucrose gradient method. Six replicates per group that underwent iTRAQ labeling and LC-MS/MS analysis for protein identification and comparison elucidated 331 differentially expressed proteins. Western analysis was used to confirm findings for selected proteins in the glutamate receptor signaling pathway, which regulates hippocampal synaptic plasticity, a cellular process critical for learning and memory. Bioinformatics were performed using knowledge-based Interactive Pathway Analysis. FID synaptosomes show altered expression of synaptic proteins-mediated cellular signalings, supporting persistent impacts of fetal iron deficiency on synaptic efficacy, which likely cause the cognitive dysfunction and neurobehavioral abnormalities. Importantly, the findings uncover previously unsuspected pathways, including neuronal nitric oxide synthase signaling, identifying additional mechanisms that may contribute to the long-term biobehavioral deficits.

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“…Analysis was performed as previously described (67). Synaptosomal fractions (10 g) resuspended in PBS and quantified by Bradford assay were resolved in a 4 -12% gradient SDS-PAGE gel (Invitrogen) and transferred onto nitrocellulose membranes (Pierce, Rockford, IL) by the Invitrogen X-cell II blot module (10 V, 8 h, 4°C).…”

Section: Methodsmentioning

confidence: 99%

Deletion of novel protein TMEM35 alters stress-related functions and impairs long-term memory in mice

Kennedy

Dimova

Dakoji

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Tran PV. Deletion of novel protein TMEM35 alters stress-related functions and impairs long-term memory in mice. Am J Physiol Regul Integr Comp Physiol 311: R166 -R178, 2016. First published May 11, 2016 doi:10.1152/ajpregu.00066.2016.-The mounting of appropriate emotional and neuroendocrine responses to environmental stressors critically depends on the hypothalamic-pituitary-adrenal (HPA) axis and associated limbic circuitry. Although its function is currently unknown, the highly evolutionarily conserved transmembrane protein 35 (TMEM35) is prominently expressed in HPA circuitry and limbic areas, including the hippocampus and amygdala. To investigate the possible involvement of this protein in neuroendocrine function, we generated tmem35 knockout (KO) mice to characterize the endocrine, behavioral, electrophysiological, and proteomic alterations caused by deletion of the tmem35 gene. While capable of mounting a normal corticosterone response to restraint stress, KO mice showed elevated basal corticosterone accompanied by increased anxiety-like behavior. The KO mice also displayed impairment of hippocampus-dependent fear and spatial memories. Given the intact memory acquisition but a deficit in memory retention in the KO mice, TMEM35 is likely required for long-term memory consolidation. This conclusion is further supported by a loss of long-term potentiation in the Schaffer collateral-CA1 pathway in the KO mice. To identify putative molecular pathways underlying alterations in plasticity, proteomic analysis of synaptosomal proteins revealed lower levels of postsynaptic molecules important for synaptic plasticity in the KO hippocampus, including PSD95 and N-methyl-D-aspartate receptors. Pathway analysis (Ingenuity Pathway Analysis) of differentially expressed synaptic proteins in tmem35 KO hippocampus implicated molecular networks associated with specific cellular and behavioral functions, including decreased long-term potentiation, and increased startle reactivity and locomotion. Collectively, these data suggest that TMEM35 is a novel factor required for normal activity of the HPA axis and limbic circuitry.HPA axis; anxiety; neural plasticity; hippocampus; proteomic THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) axis constitutes an integrated neuroendocrine network regulating physiological homeostasis (21). Although HPA activity is normally selfregulated by negative feedback via glucocorticoid stress hormone acting in the hypothalamus, additional regulation occurs through input from limbic areas, including the amygdala and hippocampus (21, 23). Furthermore, HPA output is able to modulate the normal functions of these regions and, thereby, alter behaviors associated with the limbic circuitry-namely, affective behavior, as well as learning and memory (22,47,69). For instance, a disruption of normal HPA activity, resulting from extreme or unpredictable stress, can lead to increased anxiety and memory deficits (22,31,32,36,54) and contribute to affective disorders, including post-traumatic stress disorder (PTSD) and dep...

show abstract

Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus

Cited by 47 publications

References 72 publications

Relationship between serum iron and insulin-like growth factor-I concentrations in 10-day-old calves

Relationship between serum iron and insulin-like growth factor-I concentrations in 10-day-old calves

Fetal iron deficiency alters the proteome of adult rat hippocampal synaptosomes

Deletion of novel protein TMEM35 alters stress-related functions and impairs long-term memory in mice

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