Subcutaneous Adipose Tissue from Obese and Lean Adults Does Not Release Hepcidin<i>In Vivo</i>

Tussing‐Humphreys, Lisa; Frayn, Keith N.; Smith, Steven R.; Westerman, Mark; Dennis, Andrea; Nemeth, Elizabeta; Thomson, Jessica L.; Pusatcioglu, Cenk K.

doi:10.1100/2011/634861

Cited by 15 publications

(12 citation statements)

References 41 publications

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“…Tussing‐Humphreys et al30 confirmed this result in obese women, but reported that hepatic hepcidin mRNA expression was strongly correlated with serum hepcidin, but not adipose hepcidin mRNA 16, 30. In a small sample of patients, a study reported that there was no oversecretion of hepcidin by subcutaneous adipose tissue whether the patient was obese or lean 31. Thus, the relationship that we found between serum hepcidin level and BMI in C282Y homozygous women suggests that the overproduction of hepcidin could be responsible for lower disease penetrance in the overweight cases.…”

Section: Discussionmentioning

confidence: 90%

Decreased iron burden in overweight C282Y homozygous women: Putative role of increased hepcidin production

et al. 2013

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An excess of visceral adipose tissue could be involved as a modulator of the penetrance of HFE hemochromatosis since fat mass is associated with overexpression of hepcidin and low transferrin saturation was found to be associated with being overweight in women. This study was aimed at assessing the relationship between body mass index (BMI), a surrogate marker of insulin resistance, and iron burden in HFE hemochromatosis. In all, 877 patients from a cohort of C282Y homozygotes were included in the study when BMI at diagnosis and amount of iron removed (AIR) by phlebotomy were available. No relationship between AIR and BMI was found in men, whereas 15.1% (52/345) of women with AIR <6 g had BMI !28 versus 3.9% (2/51) of women with AIR !6 g (P 5 0.03). At multivariate analysis, BMI was an independent factor negatively associated with AIR (odds ratio: 0.13; 95% confidence interval [CI]: 0.03-0.71) together with serum ferritin, serum transferrin, transferrin saturation, hemoglobin, and alanine aminotransferase. In a control group of 30 C282Y homozygous women, serum hepcidin was significantly higher in overweight (14.3 mmoL/L 6 7.1) than in lean (7.9 mmoL/L 6 4.3) women (P 5 0.0005). Conclusion: In C282Y homozygous women, BMI !28 kg/m 2 is independently associated with a lower amount of iron removed by phlebotomy. BMI is likely a modulator factor of the phenotypic expression of C282Y homozygosity, likely through an increase of circulating levels of hepcidin. (HEPATOLOGY 2013;57:1784-1792 H FE-hemochromatosis is, by far, the most common form of genetic iron-overload disease in Caucasians. 1 It is transmitted as an autosomal recessive trait and mainly related to the C282Y mutation on the HFE gene involved in the regulation of hepcidin synthesis. 2 C282Y homozygosity results in a hepdicin-deficient state 3 responsible for increased transferrin saturation and, then, parenchymal iron overload. However, its penetrance is incomplete, and according to Allen et al., 4 only 1% of C282Y homozygous women and 28% of C282Y homozygous men develop a clinical disease. Thus, C282Y homozygosity is a necessary but not a sufficient condition to promote an overt disorder. This implies that genetic and environmental factors may modulate either iron burden and/or organ damage in HFE-hemochromatosis. 5 Gender, 6,7 alcohol, 8 regimen, 9,10 drugs, 11 and polymorphisms in genes involved in iron metabolism 12-14 have been identified as such putative modulating factors.Based on the study of Laine et al., 15 who reported that, in a large screening program conducted in the general population of Brittany, France, transferrin saturation (TS) was lower in overweight than in lean C282Y homozygous women, we hypothesized that overweight might be associated with underexpression of HFE-hemochromatosis and that this might be related to the production of hepcidin by the visceral Abbreviations: AIR, amount of iron removed; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index;

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Section: Discussionmentioning

confidence: 90%

Decreased iron burden in overweight C282Y homozygous women: Putative role of increased hepcidin production

et al. 2013

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“…Tussing-Humphreys et al (60) recently found no differences between arterial and venous hepcidin across subcutaneous AT of obese and lean subjects.…”

Section: Current Status Of Knowledgementioning

confidence: 93%

“…Tussing-Humphreys et al (60) 2011 Obese (n = 9) and lean (n = 9) adults (UK) Plasma hepcidin in arterialized vs. venous blood.…”

Section: Key Findingsmentioning

confidence: 99%

Iron Biology, Immunology, Aging, and Obesity: Four Fields Connected by the Small Peptide Hormone Hepcidin

Dao

Meydani

2013

Advances in Nutrition

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Iron status and immune response become impaired in situations that involve chronic inflammation, such as obesity or aging. Little is known, however, about the additional burden that obesity may place on the iron status and immune response in the elderly. This question is relevant given the rising numbers of elderly obese (BMI >30 kg/m 2 ) individuals and the high prevalence of iron deficiency worldwide. Iron is necessary for proper function of both the innate and adaptive immune system. Hepcidin, a peptide hormone that regulates cellular iron export, is essential for the maintenance of iron homeostasis. Therefore, since immune cells require iron for proper function hepcidin may also play an important role in immune response. In this review, we summarize the evidence for hepcidin as a link between the fields of gerontology, obesity, iron biology, and immunology. We also identify several gaps in knowledge and unanswered questions pertaining to iron homeostasis and immunity in obese populations. Finally, we review studies that have shown the impact of weight loss, focusing on calorie restriction, iron homeostasis, and immunity. These studies are important both in elucidating mechanistic links between obesity and health impairments and identifying possible approaches to target immune impairment and iron deficiency as comorbidities of obesity.

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“…Hepcidin expression is also increased in chronic inflammation, by inflammatory cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β) via STAT3 (9). Hepcidin is predominantly expressed in the liver, but also in subcutaneous and visceral adipose tissue, albeit at such a low level it may not contribute to systemic hepcidin levels (6, 10). Thus, the impact of obesity-induced hepcidin upregulation and the relationship between liver vs adipose-derived hepcidin, and iron regulation in the setting of obesity is not well understood.…”

Section: Introductionmentioning

confidence: 99%

Iron Deficiency in Patients With Nonalcoholic Fatty Liver Disease Is Associated With Obesity, Female Gender, and Low Serum Hepcidin

Siddique

Nelson

Aouizerat

et al. 2014

Clinical Gastroenterology and Hepatology

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Background & Aims Iron deficiency is often observed in obese individuals. The iron regulatory hormone hepcidin is regulated by iron and cytokines IL6 and IL1β. We examine the relationship between obesity, circulating levels of hepcidin and IL6 and IL1β, and other risk factors in patients with non-alcoholic fatty liver disease (NAFLD) with iron deficiency. Methods We collected data on 675 adult subjects (>18 y old) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Subjects with transferrin saturation <20% were categorized as iron deficient, whereas those with transferrin saturation ≥20% were classified as iron normal. We assessed clinical, demographic, anthropometric, laboratory, dietary, and histologic data from patients, as well as serum levels of hepcidin and cytokines IL6 and IL1β. Univariate and multivariate analysis were used to identify risk factors for iron deficiency. Results One third of patients (231/675; 34%) were iron deficient. Obesity, diabetes, and metabolic syndrome were more common in subjects with iron deficiency (P<.01), compared with those that were iron normal. Serum levels of hepcidin were significantly lower in subjects with iron deficiency (61±45 vs 81±51 ng/mL; P<.0001). Iron deficiency was significantly associated with female sex, obesity, increased body mass index and waist circumference, presence of diabetes, lower alcohol consumption, Black or American Indian/Alaska Native race (P≤.018), and increased levels of IL6 and IL1β (6.6 vs 4.8 for iron normal; P≤.0001 and 0.45 vs 0.32 for iron normal; P≤.005). Conclusion Iron deficiency is prevalent in patients with NAFLD and associated with female sex, increased body mass index, and non-white race. Serum levels of hepcidin were lower in iron-deficient subjects, reflecting an appropriate physiological response to decreased circulating levels of iron, rather than a primary cause of iron deficiency in the setting of obesity and NAFLD.

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Subcutaneous Adipose Tissue from Obese and Lean Adults Does Not Release HepcidinIn Vivo

Cited by 15 publications

References 41 publications

Decreased iron burden in overweight C282Y homozygous women: Putative role of increased hepcidin production

Decreased iron burden in overweight C282Y homozygous women: Putative role of increased hepcidin production

Iron Biology, Immunology, Aging, and Obesity: Four Fields Connected by the Small Peptide Hormone Hepcidin

Iron Deficiency in Patients With Nonalcoholic Fatty Liver Disease Is Associated With Obesity, Female Gender, and Low Serum Hepcidin

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