Adipocyte iron regulates adiponectin and insulin sensitivity

Abstract

Iron overload is associated with increased diabetes risk. We therefore investigated the effect of iron on adiponectin, an insulin-sensitizing adipokine that is decreased in diabetic patients. In humans, normal-range serum ferritin levels were inversely associated with adiponectin, independent of inflammation. Ferritin was increased and adiponectin was decreased in type 2 diabetic and in obese diabetic subjects compared with those in equally obese individuals without metabolic syndrome. Mice fed a high-iron diet and cultured adipocytes treated with iron exhibited decreased adiponectin mRNA and protein. We found that iron negatively regulated adiponectin transcription via FOXO1-mediated repression. Further, loss of the adipocyte iron export channel, ferroportin, in mice resulted in adipocyte iron loading, decreased adiponectin, and insulin resistance. Conversely, organismal iron overload and increased adipocyte ferroportin expression because of hemochromatosis are associated with decreased adipocyte iron, increased adiponectin, improved glucose tolerance, and increased insulin sensitivity. Phlebotomy of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores. IntroductionIncreased iron stores are associated with increased risk of type 2 diabetes (1-4), gestational diabetes (5), prediabetes (6), metabolic syndrome (MetS) (7), central adiposity (8), and cardiovascular disease (9, 10). The mechanisms underlying these associations are poorly understood. The commonly used marker for total body iron stores, serum ferritin, is also responsive to inflammatory stress (11, 12), so increased ferritin in diabetes could simply reflect the inflammatory component of that disease (13). On the other hand, phlebotomy improves glycemia and MetS traits (14-17), arguing that iron may play a causal role in diabetes.The possible mediators of the association between iron and diabetes risk are not known. Decreases in both insulin secretion and sensitivity have been linked to iron. Excess iron impairs pancreatic β cell function and causes β cell apoptosis (18-21). Recent studies have also found a negative correlation between serum ferritin and the insulin-sensitizing adipokine, adiponectin (3,(22)(23)(24). The hypothesis that adiponectin links iron and insulin resistance is appealing, as decreased adiponectin levels are associated with obesity and type 2 diabetes (25) and are causally linked with insulin resistance (26).We therefore investigated the mechanisms underlying the relationships among serum ferritin, adiponectin, and MetS in mice and humans. We demonstrate in humans that the association between serum ferritin and adiponectin is independent of inflammation and that serum ferritin, even within its normal ranges, is among the best predictors of serum adiponec...

Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease

“…Contrary to our findings, a number of other studies have indicated a positive association between serum adiponectin and measures of human iron stores 9, 37, 38. These studies may be limited by the choice of surrogate for HIC.…”

“…These studies may be limited by the choice of surrogate for HIC. In those three studies, inverse correlations were noted between serum ferritin and serum adiponectin; however, this only reached statistical significance in two of the studies 9, 37. These are interesting observations that were not seen in our cohort.…”

“…Human studies demonstrate that obesity is associated not only with iron deficiency but paradoxically also with increased subcutaneous and visceral adipose tissue iron 33, 34, 35. Furthermore, increased adipocyte iron leading to a reduction in adiponectin expression has been demonstrated in a variety of mouse and adipocyte culture models 9. Taken together, it may be possible in NAFLD that iron redistributes from the liver to adipose tissue, thus contributing to insulin resistance and a reduction in serum adiponectin.…”

“…Altered adipose tissue biology and dysregulation of adipokine synthesis may promote liver injury by increased insulin resistance and also by other direct and indirect effects on hepatic and adipose tissue lipid metabolism 8. Studies in animals and tissue culture models have demonstrated an iron‐induced dysregulation of the synthesis of three adipokines with such roles, namely adiponectin, leptin, and resistin 9, 10, 11…”

“…Iron has been shown to down‐regulate adiponectin in a rodent model of selective adipocyte iron loading and also in cultured 3T3‐L1 pre‐adipocytes through decreased acetylation of the transcription factor forkhead box protein O1 (FOX01) 9. More recently, it has been demonstrated that iron down‐regulates the appetite‐suppressing hormone leptin in mice fed a high iron diet through iron‐dependent activation of cyclic adenosine monophosphate responsive element‐binding protein 10.…”