Fat and Iron Don't Mix

Ameka, Magdalene; Hasty, Alyssa H.

doi:10.20900/immunometab20200034

Cited by 9 publications

(5 citation statements)

References 48 publications

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“…The fact that serum TF, largely derived from liver, and hepatic expression of TF were unaffected by the polymorphisms in humans (1) suggests that adipocyte TF does not play a role in whole-body iron regulation, but rather may be playing a paracrine role in adipose tissue and mediating local iron trafficking. Consistent with this hypothesis, work from Dr. Hasty's laboratory has demonstrated delivery of iron from macrophages to adipocytes within adipose tissue upon highfat feeding, a process that is also associated with macrophage polarization (26). Other investigators have shown expression of the transferrin receptor in adipocytes is required for normal differentiation and thermogenesis (27).…”

Section: Discussionmentioning

confidence: 93%

A Mouse Model of Low Adipocyte Transferrin Recapitulates the Phenotype of a Human Genetic Polymorphism Associated with Insulin Sensitivity and Transferrin Expression

Lorenzo,

Das,

Harrison

et al. 2023

Preprint

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Transferrin (TF) is a key iron carrier protein. Studies in human cohorts and in cultured adipocytes suggested that decreased transferrin expression and intracellular iron in adipocytes leads to impaired insulin responsiveness and causes differential expression of genes involved in metabolism, insulin action, and obesity. While suggestive, these studies did not definitively prove in an intact organism that altering TF expression in adipocytes is sufficient to affect glucose homeostasis and insulin resistance. In this study we created a mouse model of decreased transferrin expression only in adipocytes (Trf+/-Cre+/-) to test the hypothesis that iron trafficking in adipose tissue is sufficient to affect insulin sensitivity. Area under the glucose curve (AUCg) after intraperitoneal glucose administration was increased in the Trf+/-Cre+/- mice compared to wild type (WT) mice on a normal chow diet, and the mice were slightly heavier (p=0.02 for both). Homeostasis Model of Insulin Resistance (HOMA-IR) values were also significantly higher in the Trf+/- Cre+/- mice (p<0.05). Thus, supporting our hypothesis, analysis of mice with decreased expression of TF restricted to adipocytes showed that a decrease in adipocyte TF is sufficient to affect insulin resistance, weight, and glucose homeostasis.

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Section: Discussionmentioning

confidence: 93%

A Mouse Model of Low Adipocyte Transferrin Recapitulates the Phenotype of a Human Genetic Polymorphism Associated with Insulin Sensitivity and Transferrin Expression

Lorenzo,

Das,

Harrison

et al. 2023

Preprint

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“…Iron accumulation is closely related to cell senescence [ 14 ]. The iron contents in the adipose tissues of obese individuals are significantly higher than those in the adipose tissues of individuals with normal weights [ 15 ]. Therefore, we examined the expression levels of iron metabolism-related genes in adipocytes and ASCs, respectively.…”

Section: Resultsmentioning

confidence: 99%

Transmissible Endoplasmic Reticulum Stress Mediated by Extracellular Vesicles from Adipocyte Promoting the Senescence of Adipose-Derived Mesenchymal Stem Cells in Hypertrophic Obesity

Fang

Cao

et al. 2022

Oxidative Medicine and Cellular Longevity

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Hypertrophic obesity, characterized by an excessive expansion of subcutaneous adipocytes, causes chronic inflammation and insulin resistance. It is the primary feature of obesity in middle-aged and elderly individuals. In the adipose microenvironment, a high level of endoplasmic reticulum (ER) stress and changes in the extracellular vesicle (EV) composition of adipocytes may cause the senescence and restrained differentiation of progenitor cells of adipose, including adipose-derived mesenchymal stem cells (ASCs). In this study, a hypertrophic obesity mouse model was established, and the effects of adipocytes on the ER stress and senescence of ASCs were observed in a coculture of control ASCs and hypertrophic obesity mouse adipocytes or their derived EVs. The adipocytes of hypertrophic obesity mice were treated with GW4869 or an iron chelation agent to observe the effects of EVs secreted by adipocytes and their iron contents on the ER stress and senescence of ASCs. Results showed higher ER stress level and senescence phenotypes in the ASCs from the hypertrophic obesity mice than in those from the control mice. The ER stress, senescence phenotypes, and ferritin level of ASCs can be aggravated by the coculture of ASCs with adipocytes or EVs released by them from the hypertrophic obesity mice. GW4869 or iron chelator treatment improved the ER stress and senescence of the ASCs cocultured with EVs released by the adipocytes of the hypertrophic obesity mice. Our findings suggest that EV-mediated transmissible ER stress is responsible for the senescence of ASCs in hypertrophic obesity mice.

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“…Regarding mediators that regulate iron demands in these different cell types, tissueresident macrophages may play a role in modulating local iron availability. 53,68 Tissue iron accumulation can have a harmful effect, making the body more vulnerable to ferroptosis, a pro-inflammatory and irondependent cell death process triggered by excess iron and ROS. An example of this is seen in cases of frataxin deficiency, where a significant reduction in the synthesis of iron-sulfur clusters within mitochondria disrupts the activity of mitochondrial respiratory chain complexes and aconitase.…”

Section: Iron As a Regulator Of Thermogenesismentioning

confidence: 99%

“…While iron uptake is necessary for the differentiation of white, beige, and brown adipocytes, as well as for maintaining increased mitochondrial activity in thermogenic adipocytes, reducing intracellular and mitochondrial iron levels allows for optimal and improved function in mature white adipocytes. Regarding mediators that regulate iron demands in these different cell types, tissue‐resident macrophages may play a role in modulating local iron availability 53,68 …”

Section: Introductionmentioning

confidence: 99%

Iron: The silent culprit in your adipose tissue

Moreno‐Navarrete,

Fernández‐Real

2023

Obesity Reviews

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SummaryIron plays a vital role in essential biological processes and requires precise regulation within the body. Dysregulation of iron homeostasis, characterized by increased serum ferritin levels and excessive accumulation of iron in the liver, adipose tissue, and skeletal muscle, is associated with obesity and insulin resistance. Notably, iron excess in adipose tissue promotes adipose tissue dysfunction. As optimal adipose tissue function is crucial for maintaining a healthy phenotype in obesity, a comprehensive understanding of iron homeostasis in adipose tissue is imperative for designing new therapeutic approaches to improve and prevent adipose tissue dysfunction. Here, we conducted a review of relevant studies, focusing on and providing valuable insights into the intricate interplay between iron and adipose tissue. It sheds light on the impact of iron on adipogenesis and the physiology of both white and brown adipose tissue. Furthermore, we highlight the critical role of key modulators, such as cytosolic aconitase, mitochondria, and macrophages, in maintaining iron homeostasis within adipose tissue.

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Fat and Iron Don't Mix

Cited by 9 publications

References 48 publications

A Mouse Model of Low Adipocyte Transferrin Recapitulates the Phenotype of a Human Genetic Polymorphism Associated with Insulin Sensitivity and Transferrin Expression

A Mouse Model of Low Adipocyte Transferrin Recapitulates the Phenotype of a Human Genetic Polymorphism Associated with Insulin Sensitivity and Transferrin Expression

Transmissible Endoplasmic Reticulum Stress Mediated by Extracellular Vesicles from Adipocyte Promoting the Senescence of Adipose-Derived Mesenchymal Stem Cells in Hypertrophic Obesity

Iron: The silent culprit in your adipose tissue

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