Publications by authors named "Valéria Lamounier-Zepter"

15 Publications

  • Page 1 of 1

The adipo-fibrokine activin A is associated with metabolic abnormalities and left ventricular diastolic dysfunction in obese patients.

ESC Heart Fail 2019 Apr 6;6(2):362-370. Epub 2019 Feb 6.

Clinic of Internal Medicine II, University Hospital of Regensburg, Regensburg, Germany.

Aims: Left ventricular diastolic dysfunction (LVDD) is common in obese subjects, and a relationship between epicardial adipose tissue (EAT), increased adipocytokines, and cardiovascular diseases has been reported. This study sought to examine as to whether the adipo-fibrokine activin A is a link between increased EAT, the metabolic syndrome (MetS), and LVDD in severely obese subjects.

Methods And Results: In 236 obese subjects (ø body mass index 39.8 ± 7.9 kg/m ) with a variable degree of the MetS and in 60 healthy non-obese controls (ø body mass index 24.8 ± 3.4 kg/m ), serum activin A levels were measured and correlated with parameters of the MetS, epicardial fat thickness (EFT), and echocardiographic parameters of LVDD. Activin A levels were higher in obese than in non-obese subjects (362 ± 124 vs. 301 ± 94 pg/mL, P = 0.0004), increased with the number of MetS components (from 285 ± 82 with no MetS component, 323 ± 94 with one or two MetS components, to 403 ± 131 pg/mL with ≥3 MetS components, P < 0.0001) and correlated with EFT (r = 0.41, P < 0.001). Furthermore, activin A levels were related to several parameters of LVDD [e.g. left atrial size (382 ± 117 vs. 352 125 pg/mL, P = 0.024), E/e' (394 ± 108 vs. 356 ± 127 pg/mL, P = 0.005)]. LVDD was highest in MetS obese subjects with high EFT (44.3%) compared with MetS obese subjects with low EFT (27.0%), non-MetS obese subjects with high EFT (24.2%), and non-MetS obese subjects with low EFT (10.6%, P < 0.0001).

Conclusions: In severe obesity, activin A was significantly related to EFT, MetS, and LVDD, implicating MetS-related alterations in the secretory profile of EAT in the pathogenesis of obesity-related heart disease.
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http://dx.doi.org/10.1002/ehf2.12409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437446PMC
April 2019

Aβ dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease.

Neurobiol Aging 2018 09 17;69:1-9. Epub 2018 Apr 17.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf, Germany.

We examined behaviors and neurotransmitter levels in the tgDimer mouse, a model for early Alzheimer's disease, that expresses exclusively soluble amyloid beta (Aβ) dimers and is devoid of Aβ plaques, astrogliosis, and neuroinflammation. Seven-month-old mice were subjected to tests of motor activity, attention, anxiety, habituation learning, working memory, and depression-related behaviors. They were impaired in nonselective attention and motor learning and showed anxiety- and despair-related behaviors. In 7- and 12-month-old mice, levels of acetylcholine, dopamine, and serotonin were measured in neostriatum, ventral striatum, prefrontal cortex, hippocampus, amygdala, and entorhinal cortex by high-performance liquid chromatography. The tgDimer mice had lower serotonin turnover rates in hippocampus, ventral striatum, and amygdala relative to wild type controls. The aged tgDimer mice had less hippocampal acetylcholine than adult tgDimers. Stress-test results, based on corticosterone levels, indicated an intact hypothalamus-pituitary-adrenal axis in 12-month-old mice. Since neither Aβ plaques nor astrogliosis or neuroinflammation was responsible for these phenotypes, we conclude that Aβ dimers contribute to neurotransmitter dysfunction and behavioral impairments, characteristic for the early stages of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.04.005DOI Listing
September 2018

Chronic corticosterone treatment enhances extinction-induced depression in aged rats.

Horm Behav 2016 11 12;86:21-26. Epub 2016 Sep 12.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Withdrawal and avoidance behavior are common symptoms of depression and can appear as a consequence of absence of reward, i.e. extinction-induced depression (EID). This is particularly relevant for the aged organism subjected to pronounced loss of former rewards. Avoidance of the former site of reward and increased withdrawal into a distant compartment accompany extinction of food-rewarded behavior in rodent models. During extinction, behavioral markers for re-learning dissociate from indicators of extinction-induced depression. Here we examined the effect of a chronic treatment with corticosterone (CORT), a well-known inducer of depression-related behavior, on EID in adult and aged rats. Adult (3-4months) and aged (18months) male rats were treated with CORT via drinking water for 3weeks prior to extinction of a cued food-reward task. CORT treatment increased the distance from the site of reward and decreased goal tracking behavior during extinction, especially in the aged rats. Plasma hormone levels measured before and after restraint stress showed a decline in basal ACTH- and CORT-levels after chronic CORT treatment in aged animals. The treatment significantly impaired the HPA-axis activation after acute stress in both, adult and aged animals, alike. Altogether, these findings show an enhancement of EID after chronic CORT treatment in the aged organism, which may be mediated by an impaired HPA-axis sensitivity. These findings may have special relevance for the investigation of human geriatric depression.
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http://dx.doi.org/10.1016/j.yhbeh.2016.09.003DOI Listing
November 2016

WISP1 is a novel adipokine linked to inflammation in obesity.

Diabetes 2015 Mar 3;64(3):856-66. Epub 2014 Oct 3.

Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité-Universitätsmedizin, Berlin, Germany

WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the secreted extracellular matrix-associated proteins of the CCN family and a target gene of the Wingless-type (WNT) signaling pathway. Growing evidence links the WNT signaling pathway to the regulation of adipogenesis and low-grade inflammation in obesity. We aimed to validate WISP1 as a novel adipokine. Human adipocyte differentiation was associated with increased WISP1 expression and secretion. Stimulation of human macrophages with WISP1 led to a proinflammatory response. Circulating WISP1 and WISP1 subcutaneous adipose tissue expression were regulated by weight changes in humans and mice. WISP1 expression in visceral and subcutaneous fat tissue was associated with markers of insulin resistance and inflammation in glucose-tolerant subjects. In patients with nonalcoholic fatty liver disease, we found no correlation among disease activity score, liver fat content, and WISP1 expression. Insulin regulated WISP1 expression in adipocytes in vitro but had no acute effect on WISP1 gene expression in subcutaneous fat tissue in overweight subjects who had undergone hyperinsulinemic clamp experiments. The data suggest that WISP1 may play a role in linking obesity to inflammation and insulin resistance and could be a novel therapeutic target for obesity.
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http://dx.doi.org/10.2337/db14-0444DOI Listing
March 2015

Lipoproteins and Hedgehog signalling--possible implications for the adrenal gland function.

Eur J Clin Invest 2013 Nov 2;43(11):1178-83. Epub 2013 Sep 2.

Department of Internal Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

Background: Metabolic syndrome is a common metabolic disorder that is associated with an increased risk of type 2 diabetes and cardiovascular diseases. Disturbances in adrenal steroid hormone production significantly contribute to the development of this disorder. Therefore, it is extremely important to fully understand the mechanisms governing adrenal gland function, both in physiological and pathological conditions.

Results: Recently, Sonic hedgehog has emerged as an important regulator of adrenal development, with a possible role in adult gland homeostasis. Recent work of our group shows that lipoproteins are important regulators of Hedgehog signaling; they act as carriers for the spread of Hedgehog proteins, but also contain lipid(s) that inhibit the pathway.

Conclusions: We propose that lipoproteins may affect Sonic hedgehog signaling in the adult adrenal gland at multiple levels. Understanding the interplay between lipoprotein metabolism and adrenal Hedgehog signaling may improve our understanding of how adrenal gland disorders contribute to the metabolic syndrome.
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http://dx.doi.org/10.1111/eci.12145DOI Listing
November 2013

Fatty acid binding protein 4 predicts left ventricular mass and longitudinal function in overweight and obese women.

Heart 2013 Jul 18;99(13):944-8. Epub 2013 Apr 18.

Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.

Objective: To explore whether increased adipocyte-derived serum fatty acid binding protein 4 (FABP4) predisposes to cardiac remodelling and left ventricular dysfunction in human obesity.

Design: Cross-sectional investigation.

Setting: Academic clinical research centre.

Patients: 108 overweight and obese non-diabetic women (body-mass index 33 ± 5 kg/m2).

Interventions: None.

Main Outcome Measures: Relationship between serum FABP4 and abdominal adipose tissue quantified by MRI. Relationship between serum FABP4 and left ventricular morphology and function assessed by cardiac MRI.

Results: FABP4 was independently associated with visceral abdominal adipose tissue (β=0.34, p<0.01) and subcutaneous abdominal adipose tissue (β=0.22, p<0.05). After stratification into serum FABP4 tertiles, left ventricular masses were 92 ± 16 g, 86 ± 13 g and 81 ± 12 g in women with high, intermediate and low FABP4 concentrations (p<0.01), respectively. Longitudinal systolic function was reduced by 8% in women with intermediate and high versus low FABP4 concentrations (p<0.01), whereas ejection fraction did not differ among tertiles (p=0.5). In multivariate linear analysis FABP4 remained an independent predictor of left ventricular mass (β=0.17, p<0.05) and reduced longitudinal fractional shortening (β=0.21, p<0.05).

Conclusions: In overweight and obese women, FABP4 showed an independent association with parameters of left ventricular remodelling.
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http://dx.doi.org/10.1136/heartjnl-2013-303735DOI Listing
July 2013

BMS309403 directly suppresses cardiac contractile function.

Naunyn Schmiedebergs Arch Pharmacol 2011 Sep 16;384(3):255-63. Epub 2011 Jul 16.

Medical Clinic III, University of Technology Dresden, Germany.

BMS309403, a substance used as an inhibitor of adipocyte fatty acid-binding protein, has been suggested as a new therapeutic agent for treating type 2 diabetes mellitus and atherosclerosis; however, little is known about its possible side effects. The present study investigates the effects of BMS309403 on the cardiovascular system. We used isolated perfused heart preparations and single cardiomyocytes from adult rats for contractile analysis. The Ca(2+) sensitivity of the myofilaments was investigated by using porcine cardiac skinned muscle fibers. BMS309403 induced a negative effect on the contractility of isolated perfused hearts leading to heart arrest without interfering in the electrocardiographic activity, suggesting electromechanical dissociation. Experiments with isolated cardiomyocytes showed that BMS309403 had a direct biphasic inhibitory effect on cardiomyocyte contraction, at higher concentrations by attenuating Ca(2+) levels. This negative inotropic effect does not result from a direct effect on the myofilaments. BMS309403 has an acute cardiac depressant effect in vitro. The potential therapeutic applicability of this compound requires additional consideration.
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http://dx.doi.org/10.1007/s00210-011-0667-1DOI Listing
September 2011

Adipocyte fatty acid-binding protein suppresses cardiomyocyte contraction: a new link between obesity and heart disease.

Circ Res 2009 Aug 16;105(4):326-34. Epub 2009 Jul 16.

Medical Clinic III, Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany.

Rationale: Adipocyte fatty acid-binding protein (FABP4) is a member of the intracellular lipid-binding protein family and is predominantly expressed in adipose tissue. Emerging evidence suggests that FABP4 plays a role in some aspects of the metabolic syndrome including the development of type 2 diabetes and atherosclerosis. We have recently reported that secretory products from human adipocytes directly and acutely depressed cardiac contractile function.

Objective: The purpose of this study was to identify this adipocyte-derived cardiodepressant factor.

Methods And Results: Through mass spectrometry and immunoblotting, we have identified this cardiodepressant factor as FABP4. FABP4 represents 1.8% to 8.1% of total protein secreted by adipocytes in extracellular medium. FABP4 acutely depressed shortening amplitude as well as intracellular systolic peak Ca(2+) in a dose-dependent manner in isolated rat cardiomyocytes. Heart-specific FABP isoform (FABP3) revealed a similar cardiodepressant effect. The N-terminal amino acids 1 to 20 of FABP4 could be identified as the most effective cardiodepressive domain. We could exclude any effect of FABP4 on action potential duration and L-type Ca(2+) current, suggesting a reduced excitation-contraction gain caused by FABP4 as the main inhibitory mechanism.

Conclusion: We conclude that the release of FABP4 from adipocytes may be involved in the development of cardiac contractile dysfunction of obese subjects.
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http://dx.doi.org/10.1161/CIRCRESAHA.109.200501DOI Listing
August 2009

Human adipocyte-derived factors directly inhibit cardiac contraction.

J Muscle Res Cell Motil 2008 27;29(6-8):181-4. Epub 2009 Feb 27.

Medical Clinic III, University of Dresden, Dresden, Germany.

Obesity is a major risk factor for metabolic syndrome and cardiovascular disorders. Obesity related heart disease is the most serious complication of human obesity. Despite several investigations the pathophysiological mechanisms involved remain unclear. Latest studies have emphasized the importance of adipose tissue as a highly endocrine organ which releases a wide variety of biological active substances. In this context we have recently showed that adipose tissue exerts highly potent cardiodepressant activity with an acute effect directly on cardiomyocytes contraction, thus explaining the tight association between obesity and heart failure. Further experiments led to the assumption that the activity is a protein, but some well-known adipocyte-derived proteins could be excluded to be responsible for the effect on cardiomyocytes. In the present study we investigated the production/secretion of this adipocyte-derived negative inotropic activity in more detail.
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http://dx.doi.org/10.1007/s10974-009-9172-2DOI Listing
December 2009

Adrenocortical changes and arterial hypertension in lipoatrophic A-ZIP/F-1 mice.

Mol Cell Endocrinol 2008 Jan 18;280(1-2):39-46. Epub 2007 Oct 18.

Department of Internal Medicine III, University Medical Center, University of Dresden, 01307 Dresden, Germany.

The A-ZIP/F-1 transgenic mouse is a model of lipoatrophic diabetes with severe insulin resistance, hyperglycemia and hyperlipidemia. Recently, a regulatory role of adipose tissue on adrenal gland function and blood pressure has been suggested. To further explore the importance of adipose tissue in the regulation of adrenal function and blood pressure, we studied this mouse model of lipodystrophy. A-ZIP/F-1 mice exhibit significantly elevated systolic and diastolic blood pressure values despite lack of white adipose tissue and its hormones. Furthermore, A-ZIP/F-1 lipoatrophic mice have a significant reduction of adrenal zona glomerulosa, while plasma aldosterone levels and aldosterone synthase mRNA expression remain unchanged. On the other hand, lipoatrophic mice present elevated corticosterone levels but no adrenocortical hyperplasia. Ultrastructural analysis of adrenal gland show significant alterations in adrenocortical cells, with conformational changes of mitochondrial internal membranes and high amounts of liposomes. In conclusion, lipodystrophy in A-ZIP/F-1 mice is associated with hypertension, possibly due to hypercorticosteronemia and/or others metabolic-vascular changes.
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http://dx.doi.org/10.1016/j.mce.2007.09.012DOI Listing
January 2008

Insulin resistance in hypertension and cardiovascular disease.

Best Pract Res Clin Endocrinol Metab 2006 Sep;20(3):355-67

Department of Endocrinology, Diabetes and Metabolism, University Medical Center, University of Dresden, 01307 Dresden, Germany.

Insulin resistance is not simply a problem of decreased glucose uptake in response to insulin, but a multifaceted syndrome that significantly increases the risk for cardiovascular disease. Insulin resistance is strongly associated with arterial hypertension and a pathogenetic role in the development of arterial hypertension has been suggested. One question that remains open concerns the clinical approach to insulin-resistant patients. Observational and clinical trial data suggest that lifestyle changes including weight reduction and regular physical activity can improve insulin sensitivity and reduce the incidence and mortality of cardiovascular disease. Daily physical activity of moderate intensity for 30 min has a cardioprotective effect and reduces insulin resistance, independent of the effect on body weight. A pharmacological therapy for insulin resistance reducing cardiovascular disease remains to be defined. Concerning the antihypertensive therapy of insulin-resistant hypertensive patients, most hypertensive guidelines fail to provide specific advice.
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http://dx.doi.org/10.1016/j.beem.2006.07.002DOI Listing
September 2006

Human adipocytes attenuate cardiomyocyte contraction: characterization of an adipocyte-derived negative inotropic activity.

FASEB J 2006 Aug;20(10):1653-9

Medical Clinic III, University of Dresden, Fetscherstr. 74, Dresden 01307, Germany.

The causal relationship between obesity and heart failure is broadly acknowledged; however, the pathophysiological mechanisms involved remain unclear. In this study we investigated whether human adipocytes secrete cardioactive substances that may affect cardiomyocyte contractility. We cultivated adipocytes obtained from human white adipose tissue and incubated isolated rat adult cardiomyocytes with adipocyte-conditioned or control medium. This is the first report to demonstrate that human adipocytes exhibit cardiodepressant activity with a direct and acute effect on cardiomyocyte contraction. This adipocyte-derived negative inotropic activity directly depresses shortening amplitude as well as intracellular systolic peak Ca2+ in cardiomyocytes within a few minutes. The adipocyte-derived cardiodepressant activity was dose-dependent and was completely blunted by heating or by trypsin digestion. Filtration of adipocyte-conditioned medium based on molecular mass characterized the cardiodepressant activity at between 10 and 30 kDa. In summary, adipose tissue exerts highly potent activity with an acute depressant effect directly on cardiomyocytes, which may well contribute to increased heart failure risk in overweight patients.
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http://dx.doi.org/10.1096/fj.05-5436comDOI Listing
August 2006

Fat tissue metabolism and adrenal steroid secretion.

Curr Hypertens Rep 2006 Apr;8(1):30-4

Medical Clinic III, Technical University of Dresden, MTZ, room B.00.002, Fetscherstrasse 74, 01307 Dresden, Germany.

Obesity has reached epidemic proportions in Western societies, contributing to metabolic diseases, hypertension, and vascular diseases. White adipose tissue has traditionally been regarded merely as lipid, and consequently, as energy storage. However, recent data revealed the importance of adipose tissue as a highly active endocrine organ and its involvement in the body's metabolism and homeostasis. Obesity is associated with several endocrine disorders, including adrenocortical malfunction. Because of the central role of adrenal function in the body's homeostasis, adrenal malfunction is important in the development of other obesity-related abnormalities. Therefore, in this short review, we summarize recent data on obesity-induced changes in adrenocortical mineralocorticoid, glucocorticoid, and androgen secretions and their consequences for metabolism.
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http://dx.doi.org/10.1007/s11906-006-0038-3DOI Listing
April 2006

Mineralocorticoid-stimulating activity of adipose tissue.

Best Pract Res Clin Endocrinol Metab 2005 Dec;19(4):567-75

Department of Endocrinology, Diabetes and Metabolism, University Medical Centre, University of Dresden, Germany.

Obesity is strongly associated with arterial hypertension. A positive correlation between obesity and plasma aldosterone levels has been observed by different investigators, suggesting that an abnormal secretion of aldosterone in obesity contributes to the development of arterial hypertension in obese subjects. The mechanisms proposed to explain this abnormal aldosterone production mainly involve the adipose renin-angiotensin system, an indirect effect of increased fatty acids, and direct adrenal stimulation by adipocyte secretory products. Indeed, adipose mineralocorticoid-stimulating activity was recently observed in isolated human adipocytes, suggesting a hitherto unknown direct involvement of adipose tissue in the regulation of blood pressure in obesity.
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http://dx.doi.org/10.1016/j.beem.2005.07.002DOI Listing
December 2005

Distinct contractile systems for electromechanical and pharmacomechanical coupling in smooth muscle.

Adv Exp Med Biol 2003 ;538:417-25; discussion 425-6

Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.

Electromechanical coupling by KCl depolarization of bladder preparations elicits an initial phasic and subsequent tonic contraction. Using a smooth-muscle myosin heavy chain (SM-MyHC) knock-out mouse model we could previously demonstrate, that phasic and tonic contraction of intact neonatal bladder preparations could be elicited through the recruitment of SM-MyHC and non-muscle myosin heavy chains (NM-MyHC), respectively. Inhibition of myosin light chain kinase (MLCK) by ML-7 eliminated the phasic contraction of wild-type (+/+), rather than tonic contraction of neonatal bladder strips prepared from both +/+ and homozygous SM-MyHC knock-out (-/-) mice. Pharmacomechanical coupling upon PDBu-induced activation of protein kinase C of neonatal bladder preparations elicited tonic contraction of both +/+ and -/- murine. We suggest that: i) electromechanical coupling activates both SM-MyHC and NM-MyHC systems via a ML-7 sensitive and insensitive pathway, respectively. ii) Pharmacomechanical coupling recruits part of the NM-MyHC system rather than SM-MyHC.
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http://dx.doi.org/10.1007/978-1-4419-9029-7_39DOI Listing
May 2004
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