Publications by authors named "Peter Kovacs"

408 Publications

VPNET: Variable Projection Networks.

Int J Neural Syst 2021 Oct 13:2150054. Epub 2021 Oct 13.

Institute of Signal Processing, Johannes Kepler University Linz, Altenberger str. 69, Linz 4040, Austria.

In this paper, we introduce VPNet, a novel model-driven neural network architecture based on variable projection (VP). Applying VP operators to neural networks results in learnable features, interpretable parameters, and compact network structures. This paper discusses the motivation and mathematical background of VPNet and presents experiments. The VPNet approach was evaluated in the context of signal processing, where we classified a synthetic dataset and real electrocardiogram (ECG) signals. Compared to fully connected and one-dimensional convolutional networks, VPNet offers fast learning ability and good accuracy at a low computational cost of both training and inference. Based on these advantages and the promising results obtained, we anticipate a profound impact on the broader field of signal processing, in particular on classification, regression and clustering problems.
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http://dx.doi.org/10.1142/S0129065721500544DOI Listing
October 2021

Interplay between adipose tissue secreted proteins, eating behavior and obesity.

Eur J Nutr 2021 Oct 12. Epub 2021 Oct 12.

Department of Medicine III, Division of Endocrinology, Nephrology and Rheumatology, University of Leipzig, Liebigstr. 18, 04103, Leipzig, Germany.

Purpose: Adipokines may play an important role in the complex etiology of human obesity and its metabolic complications. Here, we analyzed the relationship between 15 adipokines, eating behavior and body-mass index (BMI).

Methods: The study included 557 participants of the Sorbs (62.1% women, 37.9% men) and 3101 participants of the population-based LIFE-Adult cohorts (53.4% women, 46.4% men) who completed the German version of the Three-Factor-Eating Questionnaire to assess the eating behavior types cognitive restraint, disinhibition and hunger. Serum levels of 15 adipokines, including adiponectin, adipocyte fatty acid-binding protein (AFABP), angiopoietin-related growth factor (AGF), chemerin, fibroblast growth factor (FGF)-19, FGF-21, FGF-23, insulin-like growth factor (IGF)-1, interleukin (IL) 10, irisin, progranulin, vaspin, pro-neurotensin (pro-NT), pro-enkephalin (PENK) and leptin were measured. Based on significant correlations between several adipokines with different eating behavior items and BMI, we conducted mediation analyses, considering the eating behavior items as potential mediation variable towards BMI.

Results: Here, we found that the positive association between chemerin, AFABP or leptin and BMI in Sorbian women was mediated by higher restraint or disinhibited eating, respectively. Additionally, in Sorbian women, the negative relation between IGF-1 and BMI was mediated by higher disinhibition and the positive link between AGF and BMI by lower disinhibition. In Sorbian men, the negative relationship between PENK and BMI was mediated by lower disinhibition and hunger, whereas the negative relation between IGF-1 and BMI was mediated by higher hunger. In the LIFE-Adult women´s cohort, associations between chemerin and BMI were mediated by decreased hunger or disinhibition, respectively, whereas relations between PENK and BMI were fully mediated by decreased disinhibition.

Conclusion: Our study suggests that adipokines such as PENK, IGF-1, chemerin, AGF, AFABP and leptin might affect the development of obesity by directly modifying individual eating behavior. Given the observational nature of the study, future experimental or mechanistic work is warranted.
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http://dx.doi.org/10.1007/s00394-021-02687-wDOI Listing
October 2021

Multiomics reveal unique signatures of human epiploic adipose tissue related to systemic insulin resistance.

Gut 2021 Oct 1. Epub 2021 Oct 1.

Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden

Objective: Human white adipose tissue (AT) is a metabolically active organ with distinct depot-specific functions. Despite their locations close to the gastrointestinal tract, mesenteric AT and epiploic AT (epiAT) have only scarcely been investigated. Here, we aim to characterise these ATs in-depth and estimate their contribution to alterations in whole-body metabolism.

Design: Mesenteric, epiploic, omental and abdominal subcutaneous ATs were collected from 70 patients with obesity undergoing Roux-en-Y gastric bypass surgery. The metabolically well-characterised cohort included nine subjects with insulin sensitive (IS) obesity, whose AT samples were analysed in a multiomics approach, including methylome, transcriptome and proteome along with samples from subjects with insulin resistance (IR) matched for age, sex and body mass index (n=9). Findings implying differences between AT depots in these subgroups were validated in the entire cohort (n=70) by quantitative real-time PCR.

Results: While mesenteric AT exhibited signatures similar to those found in the omental depot, epiAT was distinct from all other studied fat depots. Multiomics allowed clear discrimination between the IS and IR states in all tissues. The highest discriminatory power between IS and IR was seen in epiAT, where profound differences in the regulation of developmental, metabolic and inflammatory pathways were observed. Gene expression levels of key molecules involved in AT function, metabolic homeostasis and inflammation revealed significant depot-specific differences with epiAT showing the highest expression levels.

Conclusion: Multi-omics epiAT signatures reflect systemic IR and obesity subphenotypes distinct from other fat depots. Our data suggest a previously unrecognised role of human epiploic fat in the context of obesity, impaired insulin sensitivity and related diseases.
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http://dx.doi.org/10.1136/gutjnl-2021-324603DOI Listing
October 2021

Multifocal Urinary Tract Metastasis of Colorectal Carcinoma.

Pathobiology 2021 Sep 15:1-7. Epub 2021 Sep 15.

Department of Pathology, University of Szeged, Szeged, Hungary.

Introduction: Secondary urinary tract tumors are uncommon findings and mainly evolve by direct invasion from adjacent organs. Actual metastatic involvement often develops in the urinary bladder, while the upper urinary tract is infrequently affected. In addition, the lungs, breast, and prostate gland are the usual primary sites. Colorectal carcinoma (CRC) may spread to the ureter directly or seeds via vascular or lymphatic channels. It may pose struggles in the differential diagnosis because CRC shares standard pathologic features with the primary adenocarcinoma of the urinary tract.

Case Presentation: We describe the case of an 81-year-old man who was referred to our hospital with a distal ureteral tumor that was treated by a ureteronephrectomy. The histopathological and genetic analysis established the diagnosis of metastatic CRC along with 3 metastases in the renal pelvis.

Conclusion: This rare case highlights the limitations of conventional histological processing, including immunohistochemistry, and it underlines the role of molecular investigations in certain circumstances.
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http://dx.doi.org/10.1159/000518967DOI Listing
September 2021

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.

Nat Genet 2021 09 2;53(9):1300-1310. Epub 2021 Sep 2.

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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http://dx.doi.org/10.1038/s41588-021-00913-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432599PMC
September 2021

A novel compound heterozygous leptin receptor mutation causes more severe obesity than in Lepr mice.

J Lipid Res 2021 Aug 11;62:100105. Epub 2021 Aug 11.

Medical Department III, Endocrinology, Nephrology, Rheumatology, CRC1052, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, Leipzig, Germany. Electronic address:

The leptin receptor (Lepr) pathway is important for food intake regulation, energy expenditure, and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chromosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-Lepr), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, Lepr develop early onset obesity and their body weight exceeds that of Lepr mice at an age of 30 weeks. Similar to Lepr mice, the Lepr model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Lepr with Lepr mice results in compound heterozygous Lepr mice, which develop even higher body weight and fat mass than both homozygous Lepr and Lepr mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.
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http://dx.doi.org/10.1016/j.jlr.2021.100105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450258PMC
August 2021

CNN-Based Classifier as an Offline Trigger for the CREDO Experiment.

Sensors (Basel) 2021 Jul 14;21(14). Epub 2021 Jul 14.

Institute of Nuclear Physics, Polish Academy of Sciences, 31-342 Kraków, Poland.

Gamification is known to enhance users' participation in education and research projects that follow the citizen science paradigm. The Cosmic Ray Extremely Distributed Observatory (CREDO) experiment is designed for the large-scale study of various radiation forms that continuously reach the Earth from space, collectively known as cosmic rays. The CREDO Detector app relies on a network of involved users and is now working worldwide across phones and other CMOS sensor-equipped devices. To broaden the user base and activate current users, CREDO extensively uses the gamification solutions like the periodical Particle Hunters Competition. However, the adverse effect of gamification is that the number of artefacts, i.e., signals unrelated to cosmic ray detection or openly related to cheating, substantially increases. To tag the artefacts appearing in the CREDO database we propose the method based on machine learning. The approach involves training the Convolutional Neural Network (CNN) to recognise the morphological difference between signals and artefacts. As a result we obtain the CNN-based trigger which is able to mimic the signal vs. artefact assignments of human annotators as closely as possible. To enhance the method, the input image signal is adaptively thresholded and then transformed using Daubechies wavelets. In this exploratory study, we use wavelet transforms to amplify distinctive image features. As a result, we obtain a very good recognition ratio of almost 99% for both signal and artefacts. The proposed solution allows eliminating the manual supervision of the competition process.
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http://dx.doi.org/10.3390/s21144804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309790PMC
July 2021

Additional Value of 18F-FDOPA Amino Acid Analog Radiotracer to Irradiation Planning Process of Patients With Glioblastoma Multiforme.

Front Oncol 2021 6;11:699360. Epub 2021 Jul 6.

Doctoral School of Health Sciences, University of Pécs, Pécs, Hungary.

Purpose: To investigate the added value of 6-(18F]-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) PET to radiotherapy planning in glioblastoma multiforme (GBM).

Methods: From September 2017 to December 2020, 17 patients with GBM received external beam radiotherapy up to 60 Gy with concurrent and adjuvant temozolamide. Target volume delineations followed the European guideline with a 2-cm safety margin clinical target volume (CTV) around the contrast-enhanced lesion+resection cavity on MRI gross tumor volume (GTV). All patients had FDOPA hybrid PET/MRI followed by PET/CT before radiotherapy planning. PET segmentation followed international recommendation: T/N 1.7 (BTV1.7) and T/N 2 (BTV2.0) SUV thresholds were used for biological target volume (BTV) delineation. For GTV-BTVs agreements, 95% of the Hausdorff distance (HD95%) from GTV to the BTVs were calculated, additionally, BTV portions outside of the GTV and coverage by the 95% isodose contours were also determined. In case of recurrence, the latest MR images were co-registered to planning CT to evaluate its location relative to BTVs and 95% isodose contours.

Results: Average (range) GTV, BTV1.7, and BTV2.0 were 46.58 (6-182.5), 68.68 (9.6-204.1), 42.89 (3.8-147.6) cm, respectively. HD95% from GTV were 15.5 mm (7.9-30.7 mm) and 10.5 mm (4.3-21.4 mm) for BTV1.7 and BTV2.0, respectively. Based on volumetric assessment, 58.8% (28-100%) of BTV1.7 and 45.7% of BTV2.0 (14-100%) were outside of the standard GTV, still all BTVs were encompassed by the 95% dose. All recurrences were confirmed by follow-up imaging, all occurred within PTV, with an additional outfield recurrence in a single case, which was not DOPA-positive at the beginning of treatment. Good correlation was found between the mean and median values of PET/CT and PET/MRI segmented volumes relative to corresponding brain-accumulated enhancement (r = 0.75; r = 0.72).

Conclusion: FDOPA PET resulted in substantial larger tumor volumes compared to MRI; however, its added value is unclear as vast majority of recurrences occurred within the prescribed dose level. Use of PET/CT signals proved to be feasible in the absence of direct segmentation possibilities of PET/MR in TPS. The added value of FDOPA may be better exploited in the context of integrated dose escalation.
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http://dx.doi.org/10.3389/fonc.2021.699360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290215PMC
July 2021

PTEN regulates adipose progenitor cell growth, differentiation, and replicative aging.

J Biol Chem 2021 Aug 14;297(2):100968. Epub 2021 Jul 14.

University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany; Institute for Metabolism and Systems Research, University of Birmingham, Birmingham, UK.

The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN hamartoma tumor syndrome (PHTS), associated with lipoma development in children. Adipose progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, whereas APCs from lipomas of patients with PHTS retain their adipogenic potential over a prolonged period. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. To investigate the role of PTEN in adipose tissue development, we performed functional assays and RNA-Seq of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR led to enhanced proliferation and differentiation of APCs. Forkhead box protein O1 (FOXO1) transcriptional activity is known to be regulated by insulin signaling, and FOXO1 was downregulated at the mRNA level while its inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis-activating transcription factor sterol regulatory element-binding protein 1 (SREBP1). SREBP1 levels were higher after PTEN knockdown and may account for the observed enhanced adipogenesis. To validate this, we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by SREBP1 downregulation. We observed that PTEN CRISPR cells showed less senescence compared with controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA-Seq of PTEN knockdown versus control cells. These results provide evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence, thereby contributing to aberrant adipose tissue growth in patients with PHTS.
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http://dx.doi.org/10.1016/j.jbc.2021.100968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350019PMC
August 2021

Environmental Factors Associated With Nitrogen Fixation Prediction in Soybean.

Front Plant Sci 2021 15;12:675410. Epub 2021 Jun 15.

Department of Agronomy, Kansas State University, Manhattan, KS, United States.

Biological nitrogen (N)-fixation is the most important source of N for soybean [ (L.) Merr.], with considerable implications for sustainable intensification. Therefore, this study aimed to investigate the relevance of environmental factors driving N-fixation and to develop predictive models defining the role of N-fixation for improved productivity and increased seed protein concentration. Using the elastic net regularization of multiple linear regression, we analyzed 40 environmental factors related to weather, soil, and crop management. We selected the most important factors associated with the relative abundance of ureides (RAU) as an indicator of the fraction of N derived from N-fixation. The most relevant RAU predictors were N fertilization, atmospheric vapor pressure deficit (VPD) and precipitation during early reproductive growth (R1-R4 stages), sowing date, drought stress during seed filling (R5-R6), soil cation exchange capacity (CEC), and soil sulfate concentration before sowing. Soybean N-fixation ranged from 60 to 98% across locations and years ( = 95). The predictive model for RAU showed relative mean square error (RRMSE) of 4.5% and an R value of 0.69, estimated cross-validation. In addition, we built similar predictive models of yield and seed protein to assess the association of RAU and these plant traits. The variable RAU was selected as a covariable for the models predicting yield and seed protein, but with a small magnitude relative to the sowing date for yield or soil sulfate for protein. The early-reproductive period VPD affected all independent variables, namely RAU, yield, and seed protein. The elastic net algorithm successfully depicted some otherwise challenging empirical relationships to assess with bivariate associations in observational data. This approach provides inference about environmental variables while predicting N-fixation. The outcomes of this study will provide a foundation for improving the understanding of N-fixation within the context of sustainable intensification of soybean production.
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http://dx.doi.org/10.3389/fpls.2021.675410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239404PMC
June 2021

Circulating bacterial signature is linked to metabolic disease and shifts with metabolic alleviation after bariatric surgery.

Genome Med 2021 Jun 22;13(1):105. Epub 2021 Jun 22.

Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.

Background: The microbiome has emerged as an environmental factor contributing to obesity and type 2 diabetes (T2D). Increasing evidence suggests links between circulating bacterial components (i.e., bacterial DNA), cardiometabolic disease, and blunted response to metabolic interventions. In this aspect, thorough next-generation sequencing-based and contaminant-aware approaches are lacking. To address this, we tested whether bacterial DNA could be amplified in the blood of subjects with obesity and high metabolic risk under strict experimental and analytical control and whether a putative bacterial signature is related to metabolic improvement after bariatric surgery.

Methods: Subjects undergoing bariatric surgery were recruited into sex- and BMI-matched subgroups with (n = 24) or without T2D (n = 24). Bacterial DNA in the blood was quantified and prokaryotic 16S rRNA gene amplicons were sequenced. A contaminant-aware approach was applied to derive a compositional microbial signature from bacterial sequences in all subjects at baseline and at 3 and 12 months after surgery. We modeled associations between bacterial load and composition with host metabolic and anthropometric markers. We further tested whether compositional shifts were related to weight loss response and T2D remission. Lastly, bacteria were visualized in blood samples using catalyzed reporter deposition (CARD)-fluorescence in situ hybridization (FISH).

Results: The contaminant-aware blood bacterial signature was associated with metabolic health. Based on bacterial phyla and genera detected in the blood samples, a metabolic syndrome classification index score was derived and shown to robustly classify subjects along their actual clinical group. T2D was characterized by decreased bacterial richness and loss of genera associated with improved metabolic health. Weight loss and metabolic improvement following bariatric surgery were associated with an early and stable increase of these genera in parallel with improvements in key cardiometabolic risk parameters. CARD-FISH allowed the detection of living bacteria in blood samples in obesity.

Conclusions: We show that the circulating bacterial signature reflects metabolic disease and its improvement after bariatric surgery. Our work provides contaminant-aware evidence for the presence of living bacteria in the blood and suggests a putative crosstalk between components of the blood and metabolism in metabolic health regulation.
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http://dx.doi.org/10.1186/s13073-021-00919-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218394PMC
June 2021

Genetics of Body Fat Distribution: Comparative Analyses in Populations with European, Asian and African Ancestries.

Genes (Basel) 2021 05 29;12(6). Epub 2021 May 29.

Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany.

Preferential fat accumulation in visceral vs. subcutaneous depots makes obese individuals more prone to metabolic complications. Body fat distribution (FD) is regulated by genetics. FD patterns vary across ethnic groups independent of obesity. Asians have more and Africans have less visceral fat compared with Europeans. Consequently, Asians tend to be more susceptible to type 2 diabetes even with lower BMIs when compared with Europeans. To date, genome-wide association studies (GWAS) have identified more than 460 loci related to FD traits. However, the majority of these data were generated in European populations. In this review, we aimed to summarize recent advances in FD genetics with a focus on comparisons between European and non-European populations (Asians and Africans). We therefore not only compared FD-related susceptibility loci identified in three ethnicities but also discussed whether known genetic variants might explain the FD pattern heterogeneity across different ancestries. Moreover, we describe several novel candidate genes potentially regulating FD, including , and identified in studies with Asian populations. It is of note that in agreement with current knowledge, most of the proposed FD candidate genes found in Asians belong to the group of developmental genes.
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http://dx.doi.org/10.3390/genes12060841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228180PMC
May 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Effects of lifestyle interventions on epigenetic signatures of liver fat: Central randomized controlled trial.

Liver Int 2021 09 28;41(9):2101-2111. Epub 2021 May 28.

Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Background And Aims: In the CENTRAL trial context, we found diverse liver fat dynamics in response to different dietary interventions. Epigenetic mechanisms may contribute to the intraindividual variation. Moreover, genetic factors are involved in developing nonalcoholic fatty-liver disease (NAFLD), a disease reflected by an increase in intrahepatic fat (IHF). In this exploratory analysis, we primarily aimed to examine the effect of lifestyle interventions on DNA-methylation of NAFLD related genes associated with IHF.

Methods: For 120 participants from the CENTRAL trial, an 18-month regimen of either low-fat (LF) or Mediterranean-low carbohydrate (MED/LC) diets, with or without physical activity (PA+/PA-), was instructed. Magnetic resonance imaging was used to measure IHF%, which was analysed for association with CpG specific DNA-methylation levels of 41 selected candidate genes. Single-nucleotide polymorphisms known to be associated with NAFLD within the studied genes were genotyped by TaqMan assays.

Results: At baseline, participants (92% men; body mass index = 30.2 kg/m ) had mean IHF of 10.7% (59% NAFLD). Baseline-IHF% was inversely correlated with DNA-methylation at individual CpGs within AC074286.1, CRACR2A, A2MP1, FARP1 (P < .05 for all multivariate models). FARP1 rs9584805 showed association with IHF, with the prevalence of NAFLD and baseline methylation level of the CpG site (cg00071727) associated with IHF%. Following 18-month lifestyle intervention, differential DNA-methylation patterns were observed between diets at cg14335324 annotated to A2MP1 (P = .04, LF vs. MED/LC), and differential DNA-methylation between PA groups within AC074286.1, CRACR2A, and FARP1 CpGs (P < .05 for all, PA-vs. PA+).

Conclusions: This study suggests epigenetic markers for IHF and potential epigenetic remodeling after long-term lifestyle interventions.
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http://dx.doi.org/10.1111/liv.14916DOI Listing
September 2021

The Effect of FGF21 and Its Genetic Variants on Food and Drug Cravings, Adipokines and Metabolic Traits.

Biomedicines 2021 Mar 29;9(4). Epub 2021 Mar 29.

Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany.

Fibroblast growth factor 21 (FGF21) is a regulator of addictive behavior. Increasing evidence suggests an impact of FGF21 on eating behavior, food and drug cravings and on other adipokines like insulin-like growth factor 1 (IGF-1) or adiponectin. We investigated the association of serum FGF21 and genetic variants with aspects of food and drug craving and obesity related metabolic parameters including serum adipokine levels. Standardized questionnaires, blood samples and anthropometric data of the Sorbs cohort ( = 1046) were analyzed using SPSS. For genetic analyses, the -locus ±10 kb was genotyped and analyzed using PLINK. Validation was conducted in a second independent cohort ( = 704). FGF21 was significantly associated with alcohol and coffee consumption, smoking and eating behavior (disinhibition). We confirmed correlations of FGF21 serum levels with IGF-1, adiponectin, pro-enkephalin, adipocyte fatty-acid-binding protein, chemerin and progranulin. genetic variants were associated with anthropometric and metabolic parameters, adipokines, food and drug craving while strongest evidence was seen with low-density lipoprotein cholesterol (LDL-C). We highlight the potential role of FGF21 in food and drug cravings and provide new insights regarding the link of FGF21 with other adipokines as well as with metabolic traits, in particular those related to lipid metabolism (LDL-C).
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http://dx.doi.org/10.3390/biomedicines9040345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065804PMC
March 2021

Impaired Intestinal Barrier and Tissue Bacteria: Pathomechanisms for Metabolic Diseases.

Front Endocrinol (Lausanne) 2021 9;12:616506. Epub 2021 Mar 9.

Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.

An intact intestinal barrier, representing the interface between inner and outer environments, is an integral regulator of health. Among several factors, bacteria and their products have been evidenced to contribute to gut barrier impairment and its increased permeability. Alterations of tight junction integrity - caused by both external factors and host metabolic state - are important for gut barrier, since they can lead to increased influx of bacteria or bacterial components (endotoxin, bacterial DNA, metabolites) into the host circulation. Increased systemic levels of bacterial endotoxins and DNA have been associated with an impaired metabolic host status, manifested in obesity, insulin resistance, and associated cardiovascular complications. Bacterial components and cells are distributed to peripheral tissues the blood stream, possibly contributing to metabolic diseases by increasing chronic pro-inflammatory signals at both tissue and systemic levels. This response is, along with other yet unknown mechanisms, mediated by toll like receptor (TLR) transduction and increased expression of pro-inflammatory cytokines, which in turn can further increase intestinal permeability leading to a detrimental positive feedback loop. The modulation of gut barrier function through nutritional and other interventions, including manipulation of gut microbiota, may represent a potential prevention and treatment target for metabolic diseases.
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http://dx.doi.org/10.3389/fendo.2021.616506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985551PMC
March 2021

[Psychological phenomena and symptoms in active and complex oncology care: challenges of interventions and rehabilitation opportunities.]

Magy Onkol 2021 Mar 14;65(1):78-88. Epub 2020 Dec 14.

Rehabilitációs Részleg, Országos Onkológiai Intézet, Onkopszichológiai Munkacsoport, Budapest, Hungary.

According to research, almost every second oncology patient experiences intense distress during their oncology treatment. The development of new medical treatment options in cancer care allows longer survival for cancer patients. Because of this, quality of life becomes an increasingly important factor during treatments. Psycho-oncological interventions include all psychosocial interventions that are designed to positively influence the patient's psychosocial adaptation and adjustment to diagnosis, treatment, and survivorship. Interventions also promote rehabilitation progress and help the emotional integration of disease-related crisis and trauma. Psycho-oncological therapies are supposed to manage cancer-related distress and other psychosocial problems by specific types of treatments or interventions. It is crucial for the medical system to deal with the psychosocial aspects of cancer care in order to identify and deal with patients' needs for better compliance and adherence to treatment. The key of personalized holistic rehabilitation is multidisciplinary teamwork during the whole healing process: sharing the emotional experience also helps to prevent healthcare workers' burnout.
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March 2021

Lifestyle weight-loss intervention may attenuate methylation aging: the CENTRAL MRI randomized controlled trial.

Clin Epigenetics 2021 03 4;13(1):48. Epub 2021 Mar 4.

Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105, Beer-Sheva, Israel.

Background: DNA methylation age (mAge), a methylation biomarker for the aging process, might serve as a more accurate predictor of morbidity and aging status than chronological age. We evaluated the role of multiple factors, including fat deposition, cardiometabolic risk factors and lifestyle weight-loss intervention, on the deviation of mAge from chronological age (mAge deviation) or 18-month change in mAge (∆mAge). In this sub-study of the CENTRAL magnetic resonance imaging weight-loss trial, we evaluated mAge by a validated 240-CpG-based prediction formula at baseline and after 18-month intervention of either low fat (LF) or mediterranean/low carbohydrate (MED/LC) diets.

Results: Among 120 CENTRAL participants with abdominal obesity or dyslipidemia, mAge (mean ± SD: 60.3 ± 7.5 years) was higher than the chronological age (48.6 ± 9.3 years) but strongly correlated (r = 0.93; p = 3.1 × 10). Participants in the lowest tertile of mAge deviation from their chronological age had significantly lower waist-circumference, visceral adipose tissue, intrahepatic fat (IHF) content, fasting-glucose and HOMA-IR, as compared with participants in the highest sex-specific residual tertile (p < 0.05 for all). IHF% remained associated with greater mAge deviation after further adjustments (β = 0.23; p = 0.02). After 18-month weight-loss lifestyle intervention, mAge remained significantly correlated with chronological age (r = 0.94, p = 1.5 × 10). mAging occurred, with no difference between lifestyle intervention groups (∆ = 0.9 ± 1.9 years in MED/LC vs. ∆ = 1.3 ± 1.9 years in LF; p = 0.2); however, we observed a mAging attenuation in successful weight losers (> 5% weight loss) vs. weight-loss failures ( ∆ = 0.6 years vs. ∆ = 1.1 years; p = 0.04), and in participants who completed the trial with healthy liver fat content (< 5% IHF) vs. participants with fatty liver (∆ = 0.6 years vs. ∆ = 1.8 years; p = 0.003). Overall, 18 months of weight-loss lifestyle intervention attenuated the mAging of the men, mainly the older, by 7.1 months than the expected (p < 0.05).

Conclusions: Lifestyle weight-loss intervention may attenuate mAging. Deviation of mAge from chronological age might be related to body fat distribution and glycemic control and could indicate biological age, health status and the risk for premature cardiometabolic diseases.

Trial Registration: ClinicalTrials.gov NCT01530724. Registered 10 February 2012, https://clinicaltrials.gov/ct2/show/study/NCT01530724 .
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http://dx.doi.org/10.1186/s13148-021-01038-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934393PMC
March 2021

A minimally destructive protocol for DNA extraction from ancient teeth.

Genome Res 2021 03 12;31(3):472-483. Epub 2021 Feb 12.

Institute of Archaeology, Research Centre for the Humanities, 1097 Budapest, Hungary.

Ancient DNA sampling methods-although optimized for efficient DNA extraction-are destructive, relying on drilling or cutting and powdering (parts of) bones and teeth. As the field of ancient DNA has grown, so have concerns about the impact of destructive sampling of the skeletal remains from which ancient DNA is obtained. Due to a particularly high concentration of endogenous DNA, the cementum of tooth roots is often targeted for ancient DNA sampling, but destructive sampling methods of the cementum often result in the loss of at least one entire root. Here, we present a minimally destructive method for extracting ancient DNA from dental cementum present on the surface of tooth roots. This method does not require destructive drilling or grinding, and, following extraction, the tooth remains safe to handle and suitable for most morphological studies, as well as other biochemical studies, such as radiocarbon dating. We extracted and sequenced ancient DNA from 30 teeth (and nine corresponding petrous bones) using this minimally destructive extraction method in addition to a typical tooth sampling method. We find that the minimally destructive method can provide ancient DNA that is of comparable quality to extracts produced from teeth that have undergone destructive sampling processes. Further, we find that a rigorous cleaning of the tooth surface combining diluted bleach and UV light irradiation seems sufficient to minimize external contaminants usually removed through the physical removal of a superficial layer when sampling through regular powdering methods.
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http://dx.doi.org/10.1101/gr.267534.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919446PMC
March 2021

ECG Beat Representation and Delineation by Means of Variable Projection.

IEEE Trans Biomed Eng 2021 Oct 20;68(10):2997-3008. Epub 2021 Sep 20.

Objective: The electrocardiogram (ECG) follows a characteristic shape, which has led to the development of several mathematical models for extracting clinically important information. Our main objective is to resolve limitations of previous approaches, that means to simultaneously cope with various noise sources, perform exact beat segmentation, and to retain diagnostically important morphological information.

Methods: We therefore propose a model that is based on Hermite and sigmoid functions combined with piecewise polynomial interpolation for exact segmentation and low-dimensional representation of individual ECG beat segments. Hermite and sigmoidal functions enable reliable extraction of important ECG waveform information while the piecewise polynomial interpolation captures noisy signal features like the baseline wander (BLW). For that we use variable projection, which allows the separation of linear and nonlinear morphological variations of the according ECG waveforms. The resulting ECG model simultaneously performs BLW cancellation, beat segmentation, and low-dimensional waveform representation.

Results: We demonstrate its BLW denoising and segmentation performance in two experiments, using synthetic and real data. Compared to state-of-the-art algorithms, the experiments showed less diagnostic distortion in case of denoising and a more robust delineation for the P and T wave.

Conclusion: This work suggests a novel concept for ECG beat representation, easily adaptable to other biomedical signals with similar shape characteristics, such as blood pressure and evoked potentials.

Significance: Our method is able to capture linear and nonlinear wave shape changes. Therefore, it provides a novel methodology to understand the origin of morphological variations caused, for instance, by respiration, medication, and abnormalities.
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http://dx.doi.org/10.1109/TBME.2021.3058781DOI Listing
October 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

DNA methylation signature in blood mirrors successful weight-loss during lifestyle interventions: the CENTRAL trial.

Genome Med 2020 11 16;12(1):97. Epub 2020 Nov 16.

Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.Box 653, 84105, Beer Sheva, Israel.

Background: One of the major challenges in obesity treatment is to explain the high variability in the individual's response to specific dietary and physical activity interventions. With this study, we tested the hypothesis that specific DNA methylation changes reflect individual responsiveness to lifestyle intervention and may serve as epigenetic predictors for a successful weight-loss.

Methods: We conducted an explorative genome-wide DNA methylation analysis in blood samples from 120 subjects (90% men, mean ± SD age = 49 ± 9 years, body mass-index (BMI) = 30.2 ± 3.3 kg/m) from the 18-month CENTRAL randomized controlled trial who underwent either Mediterranean/low-carbohydrate or low-fat diet with or without physical activity.

Results: Analyses comparing male subjects with the most prominent body weight-loss (responders, mean weight change - 16%) vs. non-responders (+ 2.4%) (N = 10 each) revealed significant variation in DNA methylation of several genes including LRRC27, CRISP2, and SLFN12 (all adj. P < 1 × 10). Gene ontology analysis indicated that biological processes such as cell adhesion and molecular functions such as calcium ion binding could have an important role in determining the success of interventional therapies in obesity. Epigenome-wide association for relative weight-loss (%) identified 15 CpGs being negatively correlated with weight change after intervention (all combined P < 1 × 10) including new and also known obesity candidates such as NUDT3 and NCOR2. A baseline DNA methylation score better predicted successful weight-loss [area under the curve (AUC) receiver operating characteristic (ROC) = 0.95-1.0] than predictors such as age and BMI (AUC ROC = 0.56).

Conclusions: Body weight-loss following 18-month lifestyle intervention is associated with specific methylation signatures. Moreover, methylation differences in the identified genes could serve as prognostic biomarkers to predict a successful weight-loss therapy and thus contribute to advances in patient-tailored obesity treatment.
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http://dx.doi.org/10.1186/s13073-020-00794-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670623PMC
November 2020

Genetics of Obesity in East Asians.

Front Genet 2020 20;11:575049. Epub 2020 Oct 20.

Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.

Obesity has become a public health problem worldwide. Compared with Europe, people in Asia tend to suffer from type 2 diabetes with a lower body mass index (BMI). Genome-wide association studies (GWASs) have identified over 750 loci associated with obesity. Although the majority of GWAS results were conducted in individuals of European ancestry, a recent GWAS in individuals of Asian ancestry has made a significant contribution to the identification of obesity susceptibility loci. Indeed, owing to the multifactorial character of obesity with a strong environmental component, the revealed loci may have distinct contributions in different ancestral genetic backgrounds and in different environments as presented through diet and exercise among other factors. Uncovering novel, yet unrevealed genes in non-European ancestries may further contribute to explaining the missing heritability for BMI. In this review, we aimed to summarize recent advances in obesity genetics in individuals of Asian ancestry. We therefore compared proposed mechanisms underlying susceptibility loci for obesity associated with individuals of European and Asian ancestries and discussed whether known genetic variants might explain ethnic differences in obesity risk. We further acknowledged that GWAS implemented in individuals of Asian ancestries have not only validated the potential role of previously specified obesity susceptibility loci but also exposed novel ones, which have been missed in the initial genetic studies in individuals of European ancestries. Thus, multi-ethnic studies have a great potential not only to contribute to a better understanding of the complex etiology of human obesity but also potentially of ethnic differences in the prevalence of obesity, which may ultimately pave new avenues in more targeted and personalized obesity treatments.
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http://dx.doi.org/10.3389/fgene.2020.575049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606890PMC
October 2020

Occurrence and characterisation of methicillin-resistant Staphylococcus aureus isolated from bovine milk in Hungary.

Acta Vet Hung 2020 09 30;68(3):236-241. Epub 2020 Sep 30.

1Department of Pathology, University of Veterinary Medicine Budapest, Üllő, Dóra major, H-2225, Hungary.

The last surveys on methicillin-resistant Staphylococcus aureus (MRSA) isolated from bovine milk in Hungary took place in the 2000s. To elucidate the genetic variability and to estimate the burden of the pathogen, MRSA from our strain collection and prospectively collected Staphylococcus aureus (SA) isolates originating from two milk hygiene laboratories were investigated. Between 2003 and 2018, 27 MRSA strains originating from 10 dairy farms were deposited and characterised. Most strains (n = 20) belonged to ST1-t127-SCCmecIV and were recovered from three unrelated farms. From other farms, variable genotypes were identified sporadically: ST22-t032-SCCmecIV from three farms; a newly described double locus variant of ST97, ST5982-t458-SCCmecIV from two farms; and ST398-t011-SCCmecIV and ST398-t011-SCCmecV from two respective farms. The prospective screening of 626 individual SA isolates originating from 42 dairy farms resulted in four (0.48 %) MRSA strains from three (7.14 %) farms. All MRSA isolates belonged to the clonal complex 398 and a novel spa-type t19251 was also identified. Most isolates were resistant to three or more antimicrobial classes. The occurrence and significance of MRSA of dairy origin seems to be unchanged in the past decade in Hungary. However, the low host specificity and multiresistance of the identified genotypes calls for periodic revision on the role and distribution of the pathogen in the Hungarian dairy sector.
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http://dx.doi.org/10.1556/004.2020.00040DOI Listing
September 2020

Multinucleated Giant Cells in Adipose Tissue Are Specialized in Adipocyte Degradation.

Diabetes 2021 02 6;70(2):538-548. Epub 2020 Nov 6.

Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, Halle, Germany

Obesity is associated with chronic low-grade inflammation of visceral adipose tissue (AT) characterized by an increasing number of AT macrophages (ATMs) and linked to type 2 diabetes. AT inflammation is histologically indicated by the formation of so-called crown-like structures, as ATMs accumulate around dying adipocytes, and the occurrence of multinucleated giant cells (MGCs). However, to date, the function of MGCs in obesity is unknown. Therefore, the aim of this study was to characterize MGCs in AT and unravel the function of these cells. We demonstrated that MGCs occurred in obese patients and after 24 weeks of a high-fat diet in mice, accompanying signs of AT inflammation and then representing ∼3% of ATMs in mice. Mechanistically, we found evidence that adipocyte death triggered MGC formation. Most importantly, MGCs in obese AT had a higher capacity to phagocytize oversized particles, such as adipocytes, as shown by live imaging of AT, 45-µm bead uptake ex vivo, and higher lipid content in vivo. Finally, we showed that interleukin-4 treatment was sufficient to increase the number of MGCs in AT, whereas other factors may be more important for endogenous MGC formation in vivo. Most importantly, our data suggest that MGCs are specialized for clearance of dead adipocytes in obesity.
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http://dx.doi.org/10.2337/db20-0293DOI Listing
February 2021

Genomic analysis of European bovine Staphylococcus aureus from clinical versus subclinical mastitis.

Sci Rep 2020 10 23;10(1):18172. Epub 2020 Oct 23.

Department Population Health Sciences, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.

Intramammary infections (IMI) with Staphylococcus aureus are a common cause of bovine mastitis and can result in both clinical (CM) or subclinical mastitis (SCM). Although bacterial isolates of S. aureus differ in their virulence potential it is largely unclear which bacterial virulence factors are responsible for increased clinical severity. We performed a genome wide association study and used a generalized linear mixed model to investigate the correlation between gene carriage, lineage and clinical outcome of IMI in a collection of S. aureus isolates from cattle with CM (n = 125) and SCM (n = 151) from 11 European countries. An additional aim was to describe the genetic variation of bovine S. aureus in Europa. The dominant lineages in our collection were clonal complex (CC) 151 (81/276, 29.3%), CC97 (54/276, 19.6%), CC479 (32/276, 11.6%) and CC398 (19/276, 6.9%). Virulence and antimicrobial resistance (AMR) gene carriage was highly associated with CC. Among a selection of nine virulence and AMR genes, CC151, CC479 and CC133 carried more virulence genes than other CCs, and CC398 was associated with AMR gene carriage. Whereas CC151, CC97 were widespread in Europe, CC479, CC398 and CC8 were only found in specific countries. Compared to CC151, CC479 was associated with CM rather than SCM (OR 3.62; 95% CI 1.38-9.50) and the other CCs were not. Multiple genes were associated with CM, but due to the clustering within CC of carriage of these genes, it was not possible to differentiate between the effect of gene carriage and CC on clinical outcome of IMI. Nevertheless, this study demonstrates that characterization of S. aureus CC and virulence genes helps to predict the likelihood of the occurrence of CM following S. aureus IMI and highlights the potential benefit of diagnostics tools to identify S. aureus CC during bovine mastitis.
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http://dx.doi.org/10.1038/s41598-020-75179-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584570PMC
October 2020

The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG.

Cell Rep 2020 10;33(3):108295

Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig 04103, Germany. Electronic address:

TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.
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http://dx.doi.org/10.1016/j.celrep.2020.108295DOI Listing
October 2020

Blurring the picture in leaky gut research: how shortcomings of zonulin as a biomarker mislead the field of intestinal permeability.

Gut 2021 Sep 9;70(9):1801-1802. Epub 2020 Oct 9.

Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at Leipzig University and University Hospital Leipzig, Leipzig, Saxony, Germany

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http://dx.doi.org/10.1136/gutjnl-2020-323026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355880PMC
September 2021

Calibrating the In Vitro-In Vivo Correlation for OATP-Mediated Drug-Drug Interactions with Rosuvastatin Using Static and PBPK Models.

Drug Metab Dispos 2020 12 9;48(12):1264-1270. Epub 2020 Oct 9.

Departments of Clinical Pharmacology (R.S., K.W.K.C., T.F., L.M.) and Drug Metabolism and Pharmacokinetics (T.F., R.L., E.P.), Genentech, Inc., South San Francisco, California; and SOLVO Biotechnology, Budapest, Hungary (P.K., A.B., E.K., Z.G.)

Organic anion-transporting polypeptide (OATP) 1B1/3-mediated drug-drug interaction (DDI) potential is evaluated in vivo with rosuvastatin (RST) as a probe substrate in clinical studies. We calibrated our assay with RST and estradiol 17--D-glucuronide (E17G)/cholecystokinin-8 (CCK8) as in vitro probes for qualitative and quantitative prediction of OATP1B-mediated DDI potential for RST. In vitro OATP1B1/1B3 inhibition using E17G and CCK8 yielded higher area under the curve (AUC) ratio (AUCR) values numerically with the static model, but all probes performed similarly from a qualitative cutoff-based prediction, as described in regulatory guidances. However, the magnitudes of DDI were not captured satisfactorily. Considering that clearance of RST is also mediated by gut breast cancer resistance protein (BCRP), inhibition of BCRP was also incorporated in the DDI prediction if the gut inhibitor concentrations were 10 × IC for BCRP inhibition. This combined static model closely predicted the magnitude of RST DDI with root-mean-square error values of 0.767-0.812 and 1.24-1.31 with and without BCRP inhibition, respectively, for in vitro-in vivo correlation of DDI. Physiologically based pharmacokinetic (PBPK) modeling was also used to simulate DDI between RST and rifampicin, asunaprevir, and velpatasvir. Predicted AUCR for rifampicin and asunaprevir was within 1.5-fold of that observed, whereas that for velpatasvir showed a 2-fold underprediction. Overall, the combined static model incorporating both OATP1B and BCRP inhibition provides a quick and simple mathematical approach to quantitatively predict the magnitude of transporter-mediated DDI for RST for routine application. PBPK complements the static model and provides a framework for studying molecules when a dynamic model is needed. SIGNIFICANCE STATEMENT: Using 22 drugs, we show that a static model for organic anion-transporting polypeptide (OATP) 1B1/1B3 inhibition can qualitatively predict potential for drug-drug interaction (DDI) using a cutoff-based approach, as in regulatory guidances. However, consideration of both OATP1B1/3 and gut breast cancer resistance protein inhibition provided a better prediction of the magnitude of the transporter-mediated DDI of these inhibitors with rosuvastatin. Based on these results, we have proposed an empirical mechanistic-static approach for a more reliable prediction of transporter-mediated DDI liability with rosuvastatin that drug development teams can leverage.
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http://dx.doi.org/10.1124/dmd.120.000149DOI Listing
December 2020
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