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

Moreno-Navarrete, José María; Ortega, Francisco; Moreno, María; Ricart, Wifredo; Fernández-Real, José Manuel

doi:10.1007/s00125-014-3298-5

Cited by 55 publications

(62 citation statements)

References 41 publications

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“…Iron is required for the adipogenesis of the 3T3-L1 preadipocytes (Moreno-Navarrete et al 2014a), and it increases the rate of adipocyte lipolysis (Rumberger et al 2004). In the mouse liver, iron significantly upregulates the transcripts of seven enzymes in the cholesterol biosynthesis pathway, resulting into cholesterol accumulation.…”

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confidence: 99%

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Wang¹,

Jiang

et al. 2016

Genetics

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The trace element iron is crucial for living organisms, since it plays essential roles in numerous cellular functions. Systemic iron overload and the elevated level of ferritin, a ubiquitous intracellular protein that stores and releases iron to maintain the iron homeostasis in cells, has long been epidemiologically associated with obesity and obesity-related diseases. However, the underlying mechanisms of this association remain unclear. Here, using Caenorhabditis elegans, we show that iron overload induces the expression of sgk-1, encoding the serum and glucocorticoid-inducible kinase, to promote the level of ferritin and fat accumulation. Mutation of cyp-23A1, encoding a homolog of human cytochrome P450 CYP7B1 that is related to neonatal hemochromatosis, further enhances the elevated expression of ftn-1, sgk-1, and fat accumulation. sgk-1 positively regulates the expression of acs-20 and vit-2, genes encoding homologs of the mammalian FATP1/4 fatty acid transport proteins and yolk lipoproteins, respectively, to facilitate lipid uptake and translocation for storage under iron overload. This study reveals a completely novel pathway in which sgk-1 plays a central role to synergistically regulate iron and lipid homeostasis, offering not only experimental evidence supporting a previously unverified link between iron and obesity, but also novel insights into the pathogenesis of iron and obesity-related human metabolic diseases. KEYWORDS iron; serum and glucocorticoid inducible kinase SGK-1; lipid uptake; obesity; C. elegans D UE to its essential roles in numerous cellular functions across nearly all living organisms, including oxygen transport, electron transport, DNA synthesis, and enzyme catalysis, exploring how iron is stored and regulated has been a growing focus in numerous fields. Dietary iron is absorbed primarily by duodenal enterocytes via the divalent metal-ion transporter 1 (DMT1) after it is reduced at the apical membrane. Subsequently, it is either stored in ferritin, which dynamically regulates iron sequestration, storage, and release or it is transported from enterocytes into the blood stream via the basolateral transporter ferroportin (Fleming and Ponka 2012). Consequently, the total amount of iron in the body is determined by its intake and storage, which are all finely regulated by many factors and signaling pathways at various levels (Fleming and Ponka 2012;Hubler et al. 2015), many of which not entirely understood.Human epidemiology studies revealed that elevated levels of ferritin may be an indication of systemic iron overload (Cook et al. 1974;Zimmermann 2008) and are positively associated with obesity (Wenzel et al. 1962;Gillum 2001;Iwasaki et al. 2005) and obesity-related diseases such as diabetes, hypertension, dyslipidaemia, or nonalcoholic fatty liver disease (Jehn et al. 2004;Bozzini et al. 2005;Mascitelli et al. 2009;Dongiovanni et al. 2011;Kim et al. 2011; see Zafon et al. 2010 for review). Precisely why elevations in ferritin levels or systemic iron overload are associated w...

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confidence: 99%

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Wang¹,

Jiang

et al. 2016

Genetics

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“…Among genes expressed at lower levels in the OIR group, some have been reported to be involved in insulin signalling and/or adipogenesis-regulating pathways, i.e. SLC2A4 encoding GLUT4, AXIN2 [25, 26], TF encoding Transferrin [27] , KLF15 [28], and CDKN2C [29]. Five genes did not display directionally consistent expression pattern in the OIR versus OIS, and obese versus lean comparisons ( AXIN2 , DLEC1 , ANKRD36B , LOC441666 , CAB39L ); these genes are besides AXIN2 poorly defined as regards function.…”

Section: Resultsmentioning

confidence: 99%

“…TF [27] , AXIN2 [25], and CDKN2C [29] . This finding is in agreement with the established association between impaired adipogenesis and insulin resistance as reviewed [49].…”

Section: Discussionmentioning

confidence: 99%

Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women

et al. 2017

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Although the mechanisms linking obesity to insulin resistance (IR) and type 2 diabetes (T2D) are not entirely understood, it is likely that alterations of adipose tissue function are involved. The aim of this study was to identify new genes controlling insulin sensitivity in adipocytes from obese women with either insulin resistant (OIR) or sensitive (OIS) adipocytes. Insulin sensitivity was first determined by measuring lipogenesis in isolated adipocytes from abdominal subcutaneous white adipose tissue (WAT) in a large observational study. Lipogenesis was measured under conditions where glucose transport was the rate limiting step and reflects in vivo insulin sensitivity. We then performed microarray-based transcriptome profiling on subcutaneous WAT specimen from a subgroup of 9 lean, 21 OIS and 18 obese OIR women. We could identify 432 genes that were differentially expressed between the OIR and OIS group (FDR ≤5%). These genes are enriched in pathways related to glucose and amino acid metabolism, cellular respiration, and insulin signaling, and include genes such as SLC2A4, AKT2, as well as genes coding for enzymes in the mitochondria respiratory chain. Two IR-associated genes, KLF15 encoding a transcription factor and SLC25A10 encoding a dicarboxylate carrier, were selected for functional evaluation in adipocytes differentiated in vitro. Knockdown of KLF15 and SLC25A10 using siRNA inhibited insulin-stimulated lipogenesis in adipocytes. Transcriptome profiling of siRNA-treated cells suggested that KLF15 might control insulin sensitivity by influencing expression of PPARG, PXMP2, AQP7, LPL and genes in the mitochondrial respiratory chain. Knockdown of SLC25A10 had only modest impact on the transcriptome, suggesting that it might directly influence insulin sensitivity in adipocytes independently of transcription due to its important role in fatty acid synthesis. In summary, this study identifies novel genes associated with insulin sensitivity in adipocytes in women independently of obesity. KFL15 and SLC25A10 are inhibitors of insulin-stimulated lipogenesis under conditions when glucose transport is the rate limiting step.

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“…As shown by in vitro 3T3-L1 differentiation models, adipocytes require iron for adipogenesis [41]. Conversely, knockdown of Tf or Ft light chain, as well as iron chelation, result in iron depletion and antiadipogenic effects in human AT explants [41]. Iron also alters adipocyte lipolysis and lipid peroxidation.…”

Section: Adipocytes and Iron: Balance Is Keymentioning

confidence: 99%

“…Conversely, mitochondrial biogenesis is upregulated during adipogenesis. Iron and IRPs have been shown to reversibly stimulate mitochondrial biogenesis and activity [41], which is also a primary mechanism for the efficacy of pharmaceutical agonists of peroxisome proliferator-activated receptor gamma commonly used to treat diabetic patients [46]. Therefore, adipocyte iron concentrations must be maintained within a proper range to allow for proper mitochondrial biogenesis and function, without being so high that oxidative stress occurs.…”

Section: Adipocytes and Iron: Balance Is Keymentioning

confidence: 99%

Iron homeostasis: a new job for macrophages in adipose tissue?

Hubler

Peterson

Hasty

2015

Trends in Endocrinology & Metabolism

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Elevated serum ferritin and increased cellular iron concentrations are risk factors for diabetes; however, the etiology of this association is unclear. Metabolic tissues such as pancreas, liver, and adipose tissue (AT), as well as the immune cells resident in these tissues, may be involved. Recent studies demonstrate that the polarization status of macrophages has important relevance to their iron handling capabilities. Furthermore, a subset of macrophages in AT have elevated iron concentrations and a gene expression profile indicative of iron handling, a capacity diminished in obesity. Because iron overload in adipocytes increases systemic insulin resistance, iron handling by AT macrophages may have relevance not only to adipocyte iron stores but also to local and systemic insulin sensitivity.

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

Cited by 55 publications

References 41 publications

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women

Iron homeostasis: a new job for macrophages in adipose tissue?

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