Auswirkungen von chronischem und akutem Stress auf die Herzfrequenzvariabilität bei Männern und postmenopausalen Frauen der gleichen Altersgruppe

Einleitung: Die körpereigene Stressreaktion schützt den Körper nicht nur, sondern kann ihn auch schädigen. Die Überlastung aller an der körpereigenen Stressreaktion beteiligten Systeme führt zu Bluthochdruck und einem höheren Herzinfarktrisiko. Ein Marker für die Überlastung aller an der körpereigenen Stressreaktion beteiligten Systeme ist die Herzfrequenzvariabilität (HFV). Das kardiovaskuläre Risiko von Frauen ist vor der Menopause niedriger als das von Männern. Ein Grund dafür ist der protektive Effekt der Östrogene. Sie beeinflussen die HFV positiv. Eine Besonderheit dieser Studie ist die Untersuchung von Frauen und der physischen Konsequenzen ihres Stresserlebens. Es wurden postmenopausale Frauen gewählt, bei denen die weiblichen Hormonkonzentrationen ein konstantes Niveau erreicht haben. Die Stresswahrnehmung wurde naturalistisch im Alltag der Versuchspersonen gemessen und mit simultan erhobenen Daten der HFV in Verbindung gebracht. Im Mittelpunkt stand die Hypothese, dass sowohl chronische als auch akute, naturalistische Stressoren mit einer Verringerung der HFV zusammenhängen. Methodik: In die Auswertung gingen die Daten von 14 postmenopausalen Frauen und 13 Männern ein. Bei ihnen wurden an durchschnittlich 5,81 Tagen 1-Kanal EKG Daten mit Hilfe eines ambulanten Brustgurtes erhoben, aus denen die HFV berechnet wurde. Die Studie umfasste zwei Teilbereiche: 1. Anhand 84 akuter Alltags-Stressphasen (50 von Frauen, 34 von Männern) und 84 dazugehöriger Alltags-Kontrollphasen, in denen die Probanden keinen Stress erlebten, konnte erforscht werden, ob und wie sich die HFV bei akutem Stress verändert. 2. Mit der Korrelation der 5-minütigen Ruhemessungen im Labor und dem chronischen Stresslevel der Probanden, durch Fragenbögen erhoben, konnte der Zusammenhang von chronischem Stress und Ruhe-HFV erforscht werden. Ergebnisse: Hinsichtlich des Prüfparameters HFPower, der parasympathische Einflüsse auf das Herz quantifiziert, fand sich eine signifikante Interaktion zwischen den Faktoren Geschlecht und Stress: Frauen zeigten während einer akuten Stressphase höhere HFV-Werte im Vergleich zu den stressfreien Kontrollphasen, wohingegen bei den Männern signifikant niedrigere HFV-Werte während der Stressphasen im Vergleich zu den stressfreien Kontrollphasen festgestellt werden konnten. Es zeigte sich außerdem, dass die durch Fragebögen erhobenen chronischen Stresslevel der letzten 2 Jahre und der letzten 4 Wochen hoch korrelierten. Entgegen der Hypothese konnte ein Zusammenhang der Stresslevel mit den HFV-Prüfvariablen während einer Ruhemessung im Labor jedoch nicht gezeigt werden. Schlussfolgerung: Frauen und Männer unterscheiden sich signifikant in kardioregulatorischen Parametern der Stressverarbeitung. Dies lässt vermuten, dass neben den Geschlechtshormonen auch die psychosoziale Stressverarbeitung Einfluss auf das kardiovaskuläre Risikoprofil nimmt. Jedoch müssen weitere Studien folgen, welche die HFV vor der Menopause bei Stress unter naturalistischen Bedingungen erforschen.Introduction: The bodily stress reaction not only protects the body but can also damage it. An overload of all systems involved in the stress reaction leads to hypertension and a higher risk of myocardial infarction. One marker for such an overload is heart rate variability (HRV). The cardiovascular risk of women before menopause is lower than that of men. One reason for this is the protective effect of the estrogens. They influence the HRV positive. A special feature of the present study is the investigation of women and the physical consequences of their stress experience. Participants were women after their menopause, when female hormone concentrations have reached constant levels. Stress perception was measured naturalistically in the everyday lives of the participants and associated with simultaneously recorded HRV data. The central hypothesis was that both chronic and acute naturalistic stressors are associated with a reduction in HRV. Methods: Data from 14 postmenopausal women and 13 men were included in the evaluation. For an average of 5.81 days, 1-channel ECG data were collected using a chest strap from which the HRV was calculated. The study’s two main analyses were: 1. Based on 84 acute everyday stress phases (50 of women, 34 of men) and 84 associated stress-free control phases, it was possible to investigate whether and how HRV changes with acute stress. 2. The relationship between chronic stress and resting HRV could be investigated with the correlation of the 5-minute rest measurements in the laboratory and the chronic stress level of the subjects, assessed by self-report questionnaires. Results: With respect to the HFPower parameter, which quantifies parasympathetic effects on the heart, a significant interaction between the factors gender and stress was found: during an acute stress phase, women showed higher HRV values compared to the stress-free control phases, while significantly lower HRV values were observed during the stress phases compared to the stress-free control phases in men. It was also shown that the chronic stress levels of the last 2 years and the last 4 weeks were highly correlated. The hypothesized negative correlation between chronic stress levels and resting HRV in the laboratory could not be found. Conclusion: Women and men differ significantly in cardioregulatory parameters of stress processing. This suggests that in addition to sex hormones, psychosocial stress processing influences the cardiovascular risk profile. However, further studies should be conducted to study the association between HRV and stress under naturalistic conditions

Evidence against a direct role of klotho in insulin resistance

The klotho gene may be involved in the aging process. Klotho is a coactivator of FGF23, a regulator of phosphate and vitamin D metabolism. It has also been reported to be downregulated in insulin resistance syndromes and paradoxically to directly inhibit IGF-1 and insulin signaling. Our aim was to study klotho's regulation and effects on insulin and IGF-1 signaling to unravel this paradox. We studied klotho tissue distribution and expression by quantitative real-time polymerase chain reaction and Western blotting in obese Zucker rats and high-fat fed Wistar rats, two models of insulin resistance. Klotho was expressed in kidneys but at much lower levels (<1.5%) in liver, muscle, brain, and adipose tissue. There were no significant differences between insulin resistant and control animals. We next produced human recombinant soluble klotho protein (KLEC) and studied its effects on insulin and IGF-1 signaling in cultured cells. In HEK293 cells, FGF23 signaling (judged by FRS2-α and ERK1/2 phosphorylation) was activated by conditioned media from KLEC-producing cells (CM-KLEC); however, IGF-1 signaling was unaffected. CM-KLEC did not inhibit IGF-1 and insulin signaling in L6 and Hep G2 cells, as judged by Akt and ERK1/2 phosphorylation. We conclude that decreased klotho expression is not a general feature of rodent models of insulin resistance. Further, the soluble klotho protein does not inhibit IGF-1 and/or insulin signaling in HEK293, L6, and HepG2 cells, arguing against a direct role of klotho in insulin signaling. However, the hypothesis that klotho indirectly regulates insulin sensitivity via FGF23 activation remains to be investigate

Preserving of postnatal leptin signaling in obesity-resistant lou/c rats following a perinatal high-fat diet

Physiological processes at adulthood, such as energy metabolism and insulin sensitivity may originate before or weeks after birth. These underlie the concept of fetal and/or neonatal programming of adult diseases, which is particularly relevant in the case of obesity and type 2 diabetes. The aim of this study was to determine the impact of a perinatal high fat diet on energy metabolism and on leptin as well as insulin sensitivity, early in life and at adulthood in two strains of rats presenting different susceptibilities to diet-induced obesity. The impact of a perinatal high fat diet on glucose tolerance and diet-induced obesity was also assessed. The development of glucose intolerance and of increased fat mass was confirmed in the obesity-prone Wistar rat, even after 28 days of age. By contrast, in obesity-resistant Lou/C rats, an improved early leptin signaling may be responsible for the lack of deleterious effect of the perinatal high fat diet on glucose tolerance and increased adiposity in response to high fat diet at adulthood. Altogether, this study shows that, even if during the perinatal period adaptation to the environment appears to be genetically determined, adaptive mechanisms to nutritional challenges occurring at adulthood can still be observed in rodents

Predictors of anemia in preschool children: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project.

Background: A lack of information on the etiology of anemia has hampered the design and monitoring of anemia-control efforts.Objective: We aimed to evaluate predictors of anemia in preschool children (PSC) (age range: 6-59 mo) by country and infection-burden category.Design: Cross-sectional data from 16 surveys (n = 29,293) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed separately and pooled by category of infection burden. We assessed relations between anemia (hemoglobin concentration &lt;110 g/L) and severe anemia (hemoglobin concentration &lt;70 g/L) and individual-level (age, anthropometric measures, micronutrient deficiencies, malaria, and inflammation) and household-level predictors; we also examined the proportion of anemia with concomitant iron deficiency (defined as an inflammation-adjusted ferritin concentration &lt;12 μg/L). Countries were grouped into 4 categories on the basis of risk and burden of infectious disease, and a pooled multivariable logistic regression analysis was conducted for each group.Results: Iron deficiency, malaria, breastfeeding, stunting, underweight, inflammation, low socioeconomic status, and poor sanitation were each associated with anemia in &gt;50% of surveys. Associations between breastfeeding and anemia were attenuated by controlling for child age, which was negatively associated with anemia. The most consistent predictors of severe anemia were malaria, poor sanitation, and underweight. In multivariable pooled models, child age, iron deficiency, and stunting independently predicted anemia and severe anemia. Inflammation was generally associated with anemia in the high- and very high-infection groups but not in the low- and medium-infection groups. In PSC with anemia, 50%, 30%, 55%, and 58% of children had concomitant iron deficiency in low-, medium-, high-, and very high-infection categories, respectively.Conclusions: Although causal inference is limited by cross-sectional survey data, results suggest anemia-control programs should address both iron deficiency and infections. The relative importance of factors that are associated with anemia varies by setting, and thus, country-specific data are needed to guide programs

Mechanisms of the Anti-Obesity Effects of Oxytocin in Diet-Induced Obese Rats

Apart from its role during labor and lactation, oxytocin is involved in several other functions. Interestingly, oxytocin- and oxytocin receptor-deficient mice develop late-onset obesity with normal food intake, suggesting that the hormone might exert a series of beneficial metabolic effects. This was recently confirmed by data showing that central oxytocin infusion causes weight loss in diet-induced obese mice. The aim of the present study was to unravel the mechanisms underlying such beneficial effects of oxytocin. Chronic central oxytocin infusion was carried out in high fat diet-induced obese rats. Its impact on body weight, lipid metabolism and insulin sensitivity was determined. We observed a dose-dependent decrease in body weight gain, increased adipose tissue lipolysis and fatty acid β-oxidation, as well as reduced glucose intolerance and insulin resistance. The additional observation that plasma oxytocin levels increased upon central infusion suggested that the hormone might affect adipose tissue metabolism by direct action. This was demonstrated using in vitro, ex vivo, as well as in vivo experiments. With regard to its mechanism of action in adipose tissue, oxytocin increased the expression of stearoyl-coenzyme A desaturase 1, as well as the tissue content of the phospholipid precursor, N-oleoyl-phosphatidylethanolamine, the biosynthetic precursor of the oleic acid-derived PPAR-alpha activator, oleoylethanolamide. Because PPAR-alpha regulates fatty acid β-oxidation, we hypothesized that this transcription factor might mediate the oxytocin effects. This was substantiated by the observation that, in contrast to its effects in wild-type mice, oxytocin infusion failed to induce weight loss and fat oxidation in PPAR-alpha-deficient animals. Altogether, these results suggest that oxytocin administration could represent a promising therapeutic approach for the treatment of human obesity and type 2 diabetes

Adjusting ferritin concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project

Background: The accurate estimation of iron deficiency is important in planning and implementing interventions. Ferritin is recommended as the primary measure of iron status, but interpretability is challenging in settings with infection and inflammation

Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia

Chronically high blood glucose (hyperglycemia) leads to diabetes, fatty liver disease, and cardiovascular disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here we show that a high fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 caused enhanced gluconeogenesis and lipogenesis in liver, a condition known as selective insulin resistance, leading to glucose intolerance. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved, non-cell-autonomous mechanism for the development of hyperglycemia

Divergent effects of oxytocin treatment of obese diabetic mice on adiposity and diabetes

Oxytocin has been suggested as a novel therapeutic against obesity, because it induces weight loss and improves glucose tolerance in diet-induced obese rodents. A recent clinical pilot study confirmed the oxytocin-induced weight-reducing effect in obese nondiabetic subjects. Nevertheless, the mechanisms involved and the impact on the main comorbidity associated with obesity, type 2 diabetes, are unknown. Lean and ob/ob mice (model of obesity, hyperinsulinemia, and diabetes) were treated for 2 weeks with different doses of oxytocin, analogues with longer half-life (carbetocin) or higher oxytocin receptor specificity ([Thr4,Gly7]-oxytocin). Food and water intake, body weight, and glycemia were measured daily. Glucose, insulin, and pyruvate tolerance, body composition, several hormones, metabolites, gene expression, as well as enzyme activities were determined. Although no effect of oxytocin on the main parameters was observed in lean mice, the treatment dose-dependently reduced food intake and body weight gain in ob/ob animals. Carbetocin behaved similarly to oxytocin, whereas [Thr4,Gly7]-oxytocin (TGOT) and a low oxytocin dose decreased body weight gain without affecting food intake. The body weight gain-reducing effect was limited to the fat mass only, with decreased lipid uptake, lipogenesis, and inflammation, combined with increased futile cycling in abdominal adipose tissue. Surprisingly, oxytocin treatment of ob/ob mice was accompanied by a worsening of basal glycemia and glucose tolerance, likely due to increased corticosterone levels and stimulation of hepatic gluconeogenesis. These results impose careful selection of the conditions in which oxytocin treatment should be beneficial for obesity and its comorbidities, and their relevance for human pathology needs to be determined