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...

This article examines children's spatial mobility in urban settings. Through data from a study of children living in contrasting urban environments, London and a lower-density new town, the article focuses on how children move around in the public realm. The data show that there are significant variations in how contemporary children use their public spaces. Children's freedom to move around their neighbourhood was greatest in the new town. Girls and minority ethnic children were more restricted in their use of urban space. Comparison with previous research suggests a decrease in independent use of public space for 10/11-year-old English children since the 1970s. It is argued that future debate about children's place in the city should move away from `the unitary public child'. Lack of attention to the different ways children use their cities will hinder advances in social policies designed to enhance participation for all children.

Insulin regulates heart metabolism through the regulation of insulin-stimulated glucose uptake. Studies have indicated that insulin can also regulate mitochondrial function. Relevant to this idea, mitochondrial function is impaired in diabetic individuals. Furthermore, the expression of Opa-1 and mitofusins, proteins of the mitochondrial fusion machinery, is dramatically altered in obese and insulin-resistant patients. Given the role of insulin in the control of cardiac energetics, the goal of this study was to investigate whether insulin affects mitochondrial dynamics in cardiomyocytes. Confocal microscopy and the mitochondrial dye MitoTracker Green were used to obtain three-dimensional images of the mitochondrial network in cardiomyocytes and L6 skeletal muscle cells in culture. Three hours of insulin treatment increased Opa-1 protein levels, promoted mitochondrial fusion, increased mitochondrial membrane potential, and elevated both intracellular ATP levels and oxygen consumption in cardiomyocytes in vitro and in vivo. Consequently, the silencing of Opa-1 or Mfn2 prevented all the metabolic effects triggered by insulin. We also provide evidence indicating that insulin increases mitochondrial function in cardiomyocytes through the Akt-mTOR-NFκB signaling pathway. These data demonstrate for the first time in our knowledge that insulin acutely regulates mitochondrial metabolism in cardiomyocytes through a mechanism that depends on increased mitochondrial fusion, Opa-1, and the Akt-mTOR-NFκB pathway.

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Abstract-Impaired insulin signaling via phosphatidylinositol 3-kinase/Akt to endothelial nitric oxide synthase (eNOS) in the vasculature has been postulated to lead to arterial dysfunction and hypertension in obesity and other insulin resistant states. To investigate this, we compared insulin signaling in the vasculature, endothelial function, and systemic blood pressure in mice fed a high-fat (HF) diet to mice with genetic ablation of insulin receptors in all vascular tissues (TTr-IR Ϫ/Ϫ ) or mice with genetic ablation of Akt1 (Akt1Ϫ/Ϫ). HF mice developed obesity, impaired glucose tolerance, and elevated free fatty acids that was associated with endothelial dysfunction and hypertension. Basal and insulin-mediated phosphorylation of extracellular signal-regulated kinase 1/2 and Akt in the vasculature was preserved, but basal and insulin-stimulated eNOS phosphorylation was abolished in vessels from HF versus lean mice. In contrast, basal vascular eNOS phosphorylation, endothelial function, and blood pressure were normal despite absent insulinmediated eNOS phosphorylation in TTr-IR Ϫ/Ϫ mice and absent insulin-mediated eNOS phosphorylation via Akt1 in Akt1Ϫ/Ϫ mice. In cultured endothelial cells, 6 hours of incubation with palmitate attenuated basal and insulinstimulated eNOS phosphorylation and NO production despite normal activation of extracellular signal-regulated kinase 1/2 and Akt. Moreover, incubation of isolated arteries with palmitate impaired endothelium-dependent but not vascular smooth muscle function. Collectively, these results indicate that lower arterial eNOS phosphorylation, hypertension, and vascular dysfunction following HF feeding do not result from defective upstream signaling via Akt, but from free fatty acid-mediated impairment of eNOS phosphorylation. Key Words: arterial insulin signaling Ⅲ hypertension Ⅲ endothelial dysfunction Ⅲ mice Ⅲ diabetes S timulation of insulin receptors in the vasculature leads to increased activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the mitogen-activated protein (MAP) kinase (eg, extracellular signaling-regulated kinase [ERK]1/2) pathway. [1][2][3][4] Insulin receptor (IR)-mediated stimulation of PI3K/Akt leads to endothelial nitric oxide (NO) synthase (eNOS) phosphorylation, NO production, and vasorelaxation. 4 -7 Insulin-mediated activation of ERK1/2 leads to endothelin (ET)-1 production, inhibition of eNOS phosphorylation, and subsequent vasocontraction. 1,4,8 Evidence from several experimental models of insulin resistance reveals impaired insulin-mediated PI3K/Aktdependent signaling in the vasculature, whereas ERK1/2 pathways are preserved or even augmented. 2,8,9 Collectively, these observations have led to the hypothesis that an imbalance in vascular insulin-mediated signaling can precipitate cardiovascular complications including endothelial dysfunction and hypertension. 1,4 Recently, it was shown that insulinmediated Akt phosphorylation was preserved, but NOmediated vasorelaxation was blunted, in arteries from obese, glucose ...