Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB

OBJECTIVE: Hypoxia affects body iron homeostasis; however, the underlying mechanisms are incompletely understood. DESIGN: Using a standardised hypoxia chamber, 23 healthy volunteers were subjected to hypoxic conditions, equivalent to an altitude of 5600 m, for 6 h. Subsequent experiments were performed in C57BL/6 mice, CREB-H knockout mice, primary hepatocytes and HepG2 cells. RESULTS: Exposure of subjects to hypoxia resulted in a significant decrease of serum levels of the master regulator of iron homeostasis hepcidin and elevated concentrations of platelet derived growth factor (PDGF)-BB. Using correlation analysis, we identified PDGF-BB to be associated with hypoxia mediated hepcidin repression in humans. We then exposed mice to hypoxia using a standardised chamber and observed downregulation of hepatic hepcidin mRNA expression that was paralleled by elevated serum PDGF-BB protein concentrations and higher serum iron levels as compared with mice housed under normoxic conditions. PDGF-BB treatment in vitro and in vivo resulted in suppression of both steady state and BMP6 inducible hepcidin expression. Mechanistically, PDGF-BB inhibits hepcidin transcription by downregulating the protein expression of the transcription factors CREB and CREB-H, and pharmacological blockade or genetic ablation of these pathways abrogated the effects of PDGF-BB toward hepcidin expression. CONCLUSIONS: Hypoxia decreases hepatic hepcidin expression by a novel regulatory pathway exerted via PDGF-BB, leading to increased availability of circulating iron that can be used for erythropoiesis

On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver

Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal1. In various pathophysiological conditions, however, erythrocyte life span is severely compromised, which threatens the organism with anemia and iron toxicity2,3. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that Ly-6Chigh monocytes ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate to ferroportin 1 (FPN1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+ Tim-4neg macrophages are transient, reside alongside embryonically-derived Tim-4high Kupffer cells, and depend on Csf1 and Nrf2. The spleen likewise recruits iron-loaded Ly-6Chigh monocytes, but these do not differentiate into iron-recycling macrophages due to the suppressive action of Csf2. Inhibiting monocyte recruitment to the liver leads to kidney and liver damage. These observations identify the liver as the primary organ supporting rapid erythrocyte removal and iron recycling and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity

Differential effects of Vav-promoter-driven overexpression of BCLX and BFL1 on lymphocyte survival and B cell lymphomagenesis

Overexpression of BCLX and BFL1/A1 has been reported in various human malignancies and is associated with poor prognosis and drug resistance, identifying these prosurvival BCL2 family members as putative drug targets. We have generated transgenic mice that express human BFL1 or human BCLX protein throughout the haematopoietic system under the control of the Vav gene promoter. Haematopoiesis is normal in both the Vav-BFL1 and Vav-BCLX transgenic (TG) mice and susceptibility to spontaneous haematopoietic malignancies is not increased. Lymphoid cells from Vav-BCLX TG mice exhibit increased resistance to apoptosis in vitro while most blood cell types form Vav-BFL1 TG mice were poorly protected. Both transgenes significantly accelerated lymphomagenesis in Eμ-MYC TG mice and, surprisingly, the Vav-BFL1 transgene was the more potent. Unexpectedly, expression of transgenic BFL1 RNA and protein is significantly elevated in B lymphoid cells of Vav-BFL1/Eμ-MYC double-transgenic compared to Vav-BFL1 mice, even during the preleukaemic phase, providing a rationale for the potent synergy. In contrast, Vav-BCLX expression was not notably different. These mouse models of BFL1 and BCLX overexpression in lymphomas should be useful tools for the testing the efficacy of novel human BFL1- and BCLX-specific inhibitors

Function outperforms morphology in the assessment of muscular contribution to insulin sensitivity in premenopausal women.

INTRODUCTION: Skeletal muscle contributes significantly to insulin sensitivity in humans. However, which non-invasive measurement best reflects this contribution remains unknown. Consequently, this paper compares morphologic and functional measurements. RESEARCH METHODS AND DESIGN: We conducted a cross-sectional analysis of 144 premenopausal women enrolled in the "Prediction, Prevention, and Sub-classification of Type 2 Diabetes" (PPSDiab) cohort study. For the analysis, we quantified insulin sensitivity by oral glucose tolerance testing and, in a subgroup of 30 women, euglycemic clamp. To assess skeletal muscle, we measured volume by magnetic resonance imaging, intramyocellular lipid content by magnetic resonance spectroscopy, and physical fitness by cardiopulmonary exercise testing. RESULTS: The mean age of the cohort was 35.7 ± 4.1 years and 94 participants (65%) had a history of gestational diabetes mellitus. Of the morphologic and functional muscle parameters, the maximum workload achieved during cardiopulmonary exercise testing associated most closely with insulin sensitivity (standardized beta = 0.39; p < .001). Peak oxygen uptake also demonstrated significant associations, whereas muscle volume and intramyocellular lipid content displayed none. CONCLUSION: Functional measurements provided a better assessment of the muscular contribution to insulin sensitivity than morphologic measurements in premenopausal women. In particular, exercise testing rendered an easy and cost-effective method applicable in clinical settings and other human studies

Association of serum myostatin with body weight, visceral fat volume, and high sensitivity C-reactive protein but not with muscle mass and physical fitness in premenopausal women.

BACKGROUND: The myokine myostatin regulates muscle mass and has been linked to insulin resistance and metabolic syndrome. However, data on its role in humans is still limited. We, therefore, investigated the associations of serum myostatin with muscle mass, physical fitness, and components of the metabolic syndrome in a cohort of premenopausal women. METHODS: We undertook a cross-sectional analysis of 233 women from the monocenter study PPSDiab, conducted in Munich, Germany. Participants had recently completed a pregnancy with or without gestational diabetes. Our analysis included medical history, anthropometrics, oral glucose tolerance testing, laboratory chemistry, cardiopulmonary exercise testing, and magnetic resonance imaging (n=142) of visceral fat volume, left quadriceps muscle mass, and muscle fat content. Serum myostatin was quantified by a competitive enzyme-linked immunosorbent assay. RESULTS: We observed positive correlations of serum myostatin with body mass index (ρ=0.235; p=0.0003), body fat percentage (ρ=0.166; p=0.011), waist circumference (ρ=0.206; p=0.002), intraabdominal fat volume (ρ=0.182; p=0.030) and high-sensitivity C-reactive protein (ρ=0.175; p=0.008). These correlations were reproduced in linear regression analyses with adjustment for age and time after delivery. We saw no correlations with muscle mass, physical fitness, insulin sensitivity, triglycerides, HDL cholesterol, and blood pressure. CONCLUSIONS: Our observation of elevated serum myostatin in women with a higher body fat percentage, visceral obesity, and elevated c-reactive protein suggests that this myokine contributes to the altered muscle-adipose tissue crosstalk in metabolic syndrome. Elevated myostatin may advance this pathophysiologic process and could also impair the efficacy of exercise interventions. Further mechanistic studies, therefore, seem warranted

A normalized real-life glucose profile after diet-induced remission of type 2 diabetes: A pilot trial.

Background/objective Type 2 diabetes related to metabolic syndrome is often partially reversible after weight loss. We conducted a pilot trial on whether complete remission to the point of a normalized real-life glucose profile, measured by continuous subcutaneous monitoring, can be achieved. Methods We conducted a mono-center, single-arm intervention trial between January 20, 2020, and January 12, 2021, in Munich, Germany. Ten participants had type 2 diabetes related to metabolic syndrome for a maximum of six years. They received a six-month lifestyle intervention including up to three months of a very-low-calorie formula diet, followed by stepwise food reintroduction and regular behavioral lifestyle counseling. The primary outcome was the status of glucose control at the end of the intervention. Complete remission was defined as normalization of the real-life glucose profile without glucose-lowering medication over at least five days. We measured anthropometric and biochemical parameters, body fat distribution by MRI, and insulin secretory reserve by an arginine stimulation test. Results Seven participants completed the trial, one reached complete remission, three achieved partial remission, and three displayed improved glucose control still in the diabetic range. A reduction of median glycosylated hemoglobin by -10 mmol/mol (-22.0 to -5.0; p = 0.016) co-occurred with weight loss of -6.4 kg (-14.2 to -3.5; p = 0.031). The insulin secretory reserve remained unchanged. Conclusions Complete remission of type 2 diabetes related to metabolic syndrome to the point of a normalized real-life glucose profile is possible through lifestyle intervention. Full intervention success remains challenging even with intensive counseling and support

Altered circulating leptin, hGH, and IGF-I in prediabetes and screening-diagnosed T2DM unrelated to metabolic syndrome in women post gestational diabetes.

Recently, we proposed two pathophysiologic subtypes of type 2 diabetes mellitus (T2DM), one related and one unrelated to metabolic syndrome. To begin to understand the pathophysiology of the subtype unrelated to metabolic syndrome, we now measured selected hormones and signaling molecules in affected individuals. In this cross-sectional analysis, we examined 138 women out of the monocenter, post gestational diabetes study PPSDiab. Of these women, 73 had prediabetes or screening-diagnosed T2DM, 40 related to metabolic syndrome and 33 unrelated. The remaining 65 women were normoglycemic controls. Our analysis included medical history, anthropometrics, oral glucose tolerance testing, laboratory chemistry, and cardiopulmonary exercise testing. In addition, plasma proinsulin/insulin ratio, growth hormone (hGH) nadir during oral glucose tolerance testing, Insulin-like Growth Factor I (IGF-I), Leptin, Resistin, Adiponectin, Fetuin-a, FGF21, and myostatin were measured. Compared to controls, women with prediabetes or screening-diagnosed T2DM unrelated to metabolic syndrome depicted higher plasma Leptin [10.47(6.6-14.57) vs. 5.52(3.15-10.02); p<0.0001] and IGF-I [193.01(171.00 - 213.30) vs. 167.97(138.77- 200.64); p=0.0008], as well as a lower hGH nadir [0.07(0.05-0.15) vs. 0.14(0.08-0.22; p<0.0001]. These differences were independent of body adiposity. Women with prediabetes or T2DM related to metabolic syndrome, in comparison to controls, displayed elevated Leptin, Fetuin-a, and FGF21, as well as reduced Adiponectin and hGH nadir. Based on our study, altered Leptin and hGH/IGF-I signaling could potentially contribute to the pathophysiology of prediabetes and T2DM unrelated to metabolic syndrome. Further mechanistic investigations of these signaling pathways in the context of lean T2DM are necessary to test causal relationships