Integrated Research and Treatment Center Adiposity Diseases

Leipzig, Germany

Integrated Research and Treatment Center Adiposity Diseases

Leipzig, Germany
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Oberbach A.,University of Leipzig | Kullnick Y.,University of Leipzig | Kullnick Y.,Integrated Research and Treatment Center Adiposity Diseases | Lehmann S.,Integrated Research and Treatment Center Adiposity Diseases | And 7 more authors.
Journal of Proteome Research | Year: 2014

Multiple reaction monitoring (MRM)-based mass spectrometric quantification of peptides and their corresponding proteins has been successfully applied for biomarker validation in serum. The option of multiplexing offers the chance to analyze various proteins in parallel, which is especially important in obesity research. Here, biomarkers that reflect multiple comorbidities and allow monitoring of therapy outcomes are required. Besides the suitability of established MRM assays for serum protein quantification, it is also feasible for analysis of tissues secreting the markers of interest. Surprisingly, studies comparing MRM data sets with established methods are rare, and therefore the biological and clinical value of most analytes remains questionable. A MRM method using nano-UPLC-MS/MS for the quantification of obesity related surrogate markers for several comorbidities in serum, plasma, visceral and subcutaneous adipose tissue was established. Proteotypic peptides for complement C3, adiponectin, angiotensinogen, and plasma retinol binding protein (RBP4) were quantified using isotopic dilution analysis and compared to the standard ELISA method. MRM method variabilities were mainly below 10%. The comparison with other MS-based approaches showed a good correlation. However, large differences in absolute quantification for complement C3 and adiponectin were obtained compared to ELISA, while less marked differences were observed for angiotensinogen and RBP4. The verification of MRM in obesity was performed to discriminate first lean and obese phenotype and second to monitor excessive weight loss after gastric bypass surgery in a seven-month follow-up. The presented MRM assay was able to discriminate obese phenotype from lean and monitor weight loss related changes of surrogate markers. However, inclusion of additional biomarkers was necessary to interpret the MRM data on obesity phenotype properly. In summary, the development of disease-related MRMs should include a step of matching the MRM data with clinically approved standard methods and defining reference values in well-sized representative age, gender, and disease-matched cohorts. © 2014 American Chemical Society.

Mueller K.,Max Planck Institute for Human Cognitive and Brain Sciences | Moller H.E.,Max Planck Institute for Human Cognitive and Brain Sciences | Horstmann A.,Max Planck Institute for Human Cognitive and Brain Sciences | Horstmann A.,Integrated Research and Treatment Center Adiposity Diseases | And 10 more authors.
Frontiers in Human Neuroscience | Year: 2015

Previous cross-sectional studies on body-weight-related alterations in brain structure revealed profound changes in the gray matter (GM) and white matter (WM) that resemble findings obtained from individuals with advancing age. This suggests that obesity may lead to structural brain changes that are comparable with brain aging. Here, we asked whether weight-loss-dependent improved metabolic and neurotrophic functioning parallels the reversal of obesity-related alterations in brain structure. To this end we applied magnetic resonance imaging (MRI) together with voxel-based morphometry and diffusion-tensor imaging in overweight to obese individuals who participated in a fitness course with intensive physical training twice a week over a period of 3 months. After the fitness course, participants presented, with inter-individual heterogeneity, a reduced body mass index (BMI), reduced serum leptin concentrations, elevated high-density lipoprotein-cholesterol (HDL-C), and alterations of serum brain-derived neurotrophic factor (BDNF) concentrations suggesting changes of metabolic and neurotrophic function. Exercise-dependent changes in BMI and serum concentration of BDNF, leptin, and HDL-C were related to an increase in GM density in the left hippocampus, the insular cortex, and the left cerebellar lobule. We also observed exercise-dependent changes of diffusivity parameters in surrounding WM structures as well as in the corpus callosum. These findings suggest that weight-loss due to physical exercise in overweight to obese participants induces profound structural brain plasticity, not primarily of sensorimotor brain regions involved in physical exercise, but of regions previously reported to be structurally affected by an increased body weight and functionally implemented in gustation and cognitive processing. © 2015 Mueller, Möller, Horstmann, Busse, Lepsien, Blüher, Stumvoll, Villringer and Pleger.

Tiepolt S.,University of Leipzig | Hesse S.,University of Leipzig | Hesse S.,Integrated Research and Treatment Center Adiposity Diseases | Patt M.,University of Leipzig | And 8 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2016

Purpose: [18F]FDG is a commonly used neuronal injury biomarker for early and differential diagnosis of dementia. Typically, the blood supply to the brain is closely coupled to glucose consumption. Early uptake of the Aβ tracer [11C]PiB on PET images is mainly determined by cerebral blood flow and shows a high correlation with [18F]FDG uptake. Uptake data for 18F-labelled Aβ PET tracers are, however, scarce. We investigated the value of early PET images using the novel Aβ tracer [18F]FBB in the diagnosis of Alzhimers disease (AD). Methods: This retrospective analysis included 22 patients with MCI or dementia who underwent dual time-point PET imaging with either [11C]PiB (11 patients) or [18F]FBB (11 patients) in routine clinical practice. Images were acquired 1 – 9 min after administration of both tracers and 40 – 70 min and 90 – 110 min after administration of [11C]PiB and [18F]FBB, respectively. The patients also underwent [18F]FDG brain PET imaging. PET data were analysed visually and semiquantitatively. Associations between early Aβ tracer uptake and dementia as well as brain atrophy were investigated. Results: Regional visual scores of early Aβ tracer and [18F]FDG PET images were significantly correlated (Spearman’s ρ = 0.780, P < 0.001). Global brain visual analysis revealed identical results between early Aβ tracer and [18F]FDG PET images. In a VOI-based analysis, the early Aβ tracer data correlated significantly with the [18F]FDG data (r = 0.779, P < 0.001), but there were no differences between [18F]FBB and [11C]PiB. Cortical SUVRs in regions typically affected in AD on early Aβ tracer and [18F]FDG PET images were correlated with MMSE scores (ρ = 0.458, P = 0.032, and ρ = 0.456, P = 0.033, respectively). A voxel-wise group-based search for areas with relatively higher tracer uptake on early Aβ tracer PET images compared with [18F]FDG PET images revealed a small cluster in the midbrain/pons; no significant clusters were found for the opposite comparison. Conclusion: Early [18F]FBB and [11C]PiB PET brain images are similar to [18F]FDG PET images in AD patients, and these tracers could potentially be used as biomarkers in place of [18F]FDG. Thus, Aβ tracer PET imaging has the potential to provide biomarker information on AD pathology and neuronal injury. The potential of this approach for supporting the diagnosis of AD needs to be confirmed in prospective studies in larger cohorts. © 2016 Springer-Verlag Berlin Heidelberg

Himmerich H.,University of Leipzig | Himmerich H.,Integrated Research and Treatment Center Adiposity Diseases | Minkwitz J.,University of Leipzig | Minkwitz J.,Integrated Research and Treatment Center Adiposity Diseases | Kirkby K.C.,University of Tasmania
Endocrine, Metabolic and Immune Disorders - Drug Targets | Year: 2015

Weight gain and metabolic disturbances are common side effects during psychopharmacological treatment with specific antipsychotics and antidepressants. The antipsychotics clozapine and olanzapine, and antidepressants tricyclics and mirtazapine have a high risk of inducing weight gain. Recently discovered pathophysiological mechanisms include antihistaminergic effects, activation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK), modulation of hormonal signaling of ghrelin and leptin, changes in the production of cytokines such as tumor necrosis factor-alpha (TNF)-alpha and adipokines such as adiponektin, and the impact of genes, in particular the melanocortin 4 receptor (MC4R), serotonin 2C receptor (HTR2C), leptin, neuropeptide Y (NPY) and cannabinoid receptor 1 (CNR1) genes. Metabolic changes associated with weight gain include disturbances of glucose and lipid metabolism. Clozapine and olanzapine may, in addition to mechanisms resulting from weight gain, impair glucose metabolism by blockade of the muscarinic M3 receptor (M3R). Antidepressants associated with weight gain appear to have fewer unfavourable effects on glucose and lipid metabolism than the second-generation antipsychotics clozapine and olanzapine. To assess the risk of weight gain and its consequences for the patient’s health, assessing body weight changes and metabolic monitoring in the first week of treatment as well as in long-term treatment is recommended. © 2015 Bentham Science Publishers.

Elbelt U.,Charité - Medical University of Berlin | Schuetz T.,Integrated Research and Treatment Center Adiposity Diseases | Lochs H.,Innsbruck Medical University
Nutrition in Clinical Practice | Year: 2012

Background: The measurement of resting energy expenditure (REE) in an ambulatory setting raises methodological problems. Therefore, the use of predictive equations for the estimation of REE is common. Alternatively, the measurement of sleeping energy expenditure (SEE) has been proposed. The authors retrospectively analyzed data on SEE assessed with a portable armband (PA) device in an ambulatory setting and evaluated this approach against predictive equations and REE measured by indirect calorimetry (IC). Methods: REE was measured with IC, and SEE was assessed with the PA using standardized conditions in 81 participants (aged 46 ± 13 years) over a wide range of body weight (mean body mass index [BMI] 36.4 ± 9.3 kg/m2; range, 21.6-55.7). Results: SEE (1756 ± 393 kcal/d) was 7.6% higher than REE (1632 ± 346 kcal/d) (P <.001). This difference (123 ± 214 kcal/d) was smaller than that using the predictive equation for REE by Harris and Benedict (207 ± 217 kcal/d) and the BMI group-specific equations according to Müller et al (209 ± 190 kcal/d). Linear regression analysis was significant (r2 = 0.705; P <.001). SEE showed similar 95% confidence intervals compared with both of the predictive equations. Conclusions: The described standardized assessment of SEE by a PA device appears to be a promising approach to estimate REE in an ambulatory setting. SEE reflects REE at least as precisely as the predictive equations. © 2012 American Society for Parenteral and Enteral Nutrition.

Mueller K.,Max Planck Institute for Human Cognitive and Brain Sciences | Horstmann A.,Max Planck Institute for Human Cognitive and Brain Sciences | Horstmann A.,Integrated Research and Treatment Center Adiposity Diseases | Moller H.E.,Max Planck Institute for Human Cognitive and Brain Sciences | And 9 more authors.
PLoS ONE | Year: 2014

Obesity is known to affect the brains gray matter (GM) and white matter (WM) structure but the interrelationship of such changes remains unclear. Here we used T1-weighted magnetic resonance imaging (MRI) in combination with voxel-based morphometry (VBM) and diffusion-tensor imaging (DTI) with tract-based spatial statistics (TBSS) to assess the relationship between obesity-associated alterations of gray matter density (GMD) and anisotropic water diffusion in WM, respectively. In a small cohort of lean to obese women, we confirmed previous reports of obesityassociated alterations of GMD in brain regions involved in executive control (i.e., dorsolateral prefrontal cortex, DLPFC) and habit learning (i.e., dorsal striatum). Gray matter density alterations of the DLPFC were negatively correlated with radial diffusivity in the entire corpus callosum. Within the genu of the corpus callosum we found a positive correlation with axial diffusivity. In posterior region and inferior areas of the body of the corpus callosum, axial diffusivity correlated negatively with altered GMD in the dorsal striatum. These findings suggest that, in women, obesityrelated alterations of GMD in brain regions involved in executive control and habit learning might relate to alterations of associated WM fiber bundles within the corpus callosum. © 2014 Mueller et al.

Kosacka J.,University of Leipzig | Kern M.,University of Leipzig | Kloting N.,University of Leipzig | Kloting N.,Integrated Research and Treatment Center Adiposity Diseases | And 9 more authors.
Molecular and Cellular Endocrinology | Year: 2015

Background: Pathophysiology of obesity is closely associated with enhanced autophagy in adipose tissue (AT). Autophagic process can promote survival or activate cell death. Therefore, we examine the occurrence of autophagy in AT of type 2 diabetes (T2D) patients in comparison to obese and lean individuals without diabetes. Methodology/principal findings: Numerous autophagosomes accumulated within adipocytes were visualized by electron transmission microscopy and by immunofluorescence staining for autophagy marker LC3 in obese and T2D patients. Increased autophagy was demonstrated by higher LC3-II/LC3-I ratio, up-regulated expression of LC3 and Atg5 mRNA, along with decreased p62 and mTOR protein levels. Increased autophagy occurred together with AT inflammation. Conclusions: Our data suggest fat depot-related differences in autophagy regulation. In subcutaneous AT, increased autophagy is accompanied by increased markers of apoptosis in patients with obesity independently of T2D. In contrast, in visceral AT only in T2D patients increased autophagy was related to higher markers of apoptosis. © 2015 Elsevier Ireland Ltd.

Mueller K.,Max Planck Institute for Human Cognitive and Brain Sciences | Anwander A.,Max Planck Institute for Human Cognitive and Brain Sciences | Moller H.E.,Max Planck Institute for Human Cognitive and Brain Sciences | Horstmann A.,Max Planck Institute for Human Cognitive and Brain Sciences | And 13 more authors.
PLoS ONE | Year: 2011

Several studies have shown that obesity is associated with changes in human brain function and structure. Since women are more susceptible to obesity than men, it seems plausible that neural correlates may also be different. However, this has not been demonstrated so far. To address this issue, we systematically investigated the brain's white matter (WM) structure in 23 lean to obese women (mean age 25.5 y, std 5.1 y; mean body mass index (BMI) 29.5 kg/m2, std 7.3 kg/m2) and 26 lean to obese men (mean age 27.1 y, std 5.0 y; mean BMI 28.8 kg/m2, std 6.8 kg/m2) with diffusion-weighted magnetic resonance imaging (MRI). There was no significant age (p>0.2) or BMI (p>0.7) difference between female and male participants. Using tract-based spatial statistics, we correlated several diffusion parameters including the apparent diffusion coefficient, fractional anisotropy (FA), as well as axial (λ∥) and radial diffusivity (λ⊥) with BMI and serum leptin levels. In female and male subjects, the putative axon marker λ∥ was consistently reduced throughout the corpus callosum, particularly in the splenium (r = -0.62, p

Meyer P.M.,University of Leipzig | Tiepolt S.,University of Leipzig | Barthel H.,University of Leipzig | Hesse S.L.,University of Leipzig | And 3 more authors.
Quarterly Journal of Nuclear Medicine and Molecular Imaging | Year: 2014

The α4β2∗ nicotinic acetylcholine receptors (α4β2∗-nAChR) are highly abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as memory, learning and attention as well as mood and motor function. Post mortem studies suggest that abnormalities of α4β2∗-nAChRs are closely linked to histopathological hallmarks of Alzheimer's disease (AD), such as amyloid aggregates/oligomers and tangle pathology and of Parkinson's disease (PD) such as Lewy body pathology and the nigrostriatal dopaminergic deficit. In this review we summarize and discuss nicotinic receptor imaging findings of 2-[18F]FA-85380 PET, ["C]nicotine PET and 5-[123I]IA-85380 SPECT studies investigating α4β2∗-nAChR binding in vivo and their; relationship to mental dysfunction in the brain of patients with AD and patients out of the spectrum of Lewy body disorders such as PD and Lewy body dementia (DLB). Furthermore, recent developments of novel α4β2∗-nAChR-specific PET radioligands, such as (-)[18F]Flubatine or [18F]AZAN are summarized. We conclude that α4β2∗-nAChR-specific PET might become a biomarker for early diagnostics and drug developments in patients with AD, DLB and PD, even at early or prodromal stages.

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