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Article ; Online: FTO Obesity Risk Variants Are Linked to Adipocyte IRX3 Expression and BMI of Children - Relevance of FTO Variants to Defend Body Weight in Lean Children?

Kathrin Landgraf / Markus Scholz / Peter Kovacs / Wieland Kiess / Antje Körner

PLoS ONE, Vol 11, Iss 8, p e

2016 Volume 0161739

Abstract: Genome-wide association studies have identified variants within the FTO (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene loci. Recent evidence suggests that variants in FTO directly affect ...

Abstract	Genome-wide association studies have identified variants within the FTO (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene loci. Recent evidence suggests that variants in FTO directly affect human adipocyte function through targeting IRX3 and IRX5 and thermogenesis regulation.We addressed the relevance of this proposed FTO-IRX pathway in adipose tissue (AT) of children.Expression of IRX3 was higher in adipocytes compared to SVF. We found increased adipocyte-specific expression of IRX3 and IRX5 with the presence of the FTO risk haplotype in lean children, whereas it was unaffected by risk variants in obese peers. We further show that IRX3 expression was elevated in isolated adipocytes and AT of lean compared to obese children, particularly in UCP1-negative adipocytes, and inversely correlated with BMI SDS. Independent of BMI, IRX3 expression in adipocytes was significantly related to adipocyte hypertrophy, and subsequent associations with AT inflammation and HOMA-IR in the children.One interpretation of our observation of FTO risk variants linked to IRX3 expression and adipocyte size restricted to lean children, along with the decreased IRX3 expression in obese compared to lean peers, may reflect a defense mechanism for protecting body-weight, which is pertinent for lean children.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dynamic alterations in linear growth and endocrine parameters in children with obesity and height reference values

Elena Kempf / Mandy Vogel / Tim Vogel / Jürgen Kratzsch / Kathrin Landgraf / Andreas Kühnapfel / Ruth Gausche / Daniel Gräfe / Elena Sergeyev / Roland Pfäffle / Wieland Kiess / Juraj Stanik / Antje Körner

EClinicalMedicine, Vol 37, Iss , Pp 100977- (2021)

2021

Abstract: Background: Obesity can affect linear growth of children but there is uncertainty regarding the dynamics and potential causes. Methods: In the population-based LIFE Child and the obesity-enriched Leipzig Obesity Childhood cohorts (8,629 children, 37,493 ... ...

Abstract	Background: Obesity can affect linear growth of children but there is uncertainty regarding the dynamics and potential causes. Methods: In the population-based LIFE Child and the obesity-enriched Leipzig Obesity Childhood cohorts (8,629 children, 37,493 measurements), recruited from 1999 to 2018 in Germany, we compared height, growth, and endocrine parameters between normal-weight and children with obesity (0–20 years). Derived from the independent German CrescNet registry (12,703 children) we generated height reference values specific for children with obesity (data collected from 1999 to 2020). Findings: Children with obesity were significantly taller than normal-weight peers, differing at maximum by 7·6 cm (1·4 height, standard deviation scores or SDS) at age 6–8 years. Already at birth, children with obesity were slightly taller and thereafter had increased growth velocities by up to 1·2 cm/year. This growth acceleration was unrelated to parental height, but was accompanied by increased levels of insulin-like growth factor-1 (IGF-1), insulin and leptin. During puberty, children with obesity showed a catch-down in height SDS. The reduction in pubertal growth velocity by up to 25% coincided with a decrease in levels of IGF-1 (by 17%) and testosterone (by 62%) in boys and estradiol (by 37%) in girls. We confirmed these alterations in growth in the independent CrescNet cohort and furthermore provide height reference values for children with obesity for open access. Interpretation: Dynamics of linear growth are altered distinctively in different developmental phases in children with obesity. Early emergence before other profound comorbidities implies predisposition, environmental, and/or endocrine factors affecting growth in early life. Height reference values for children with obesity may enhance the precision of clinical health surveillance. Funding: German Research Foundation, German Diabetes Association, EU, ESF, ERDF, State of Saxony, ESPE, Hexal, Novo Nordisk, Pfizer Pharma.
Keywords	Children ; Obesity ; Height ; Growth velocity ; IGF-1 ; Insulin ; Medicine (General) ; R5-920
Subject code	796
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: An MRM-Based Multiplexed Quantification Assay for Human Adipokines and Apolipoproteins

Laura Krieg / Alexandra Schaffert / Matthias Kern / Kathrin Landgraf / Martin Wabitsch / Annette G. Beck-Sickinger / Antje Körner / Matthias Blüher / Martin von Bergen / Kristin Schubert

Molecules, Vol 25, Iss 4, p

2020 Volume 775

Abstract: Adipokines and apolipoproteins are key regulators and potential biomarkers in obesity and associated diseases and their quantitative assessment is crucial for functional analyses to understand disease mechanisms. Compared to routinely used ELISAs, ... ...

Abstract	Adipokines and apolipoproteins are key regulators and potential biomarkers in obesity and associated diseases and their quantitative assessment is crucial for functional analyses to understand disease mechanisms. Compared to routinely used ELISAs, multiple reaction monitoring (MRM)-based mass spectrometry allows multiplexing and detection of proteins for which antibodies are not available. Thus, we established an MRM method to quantify 9 adipokines and 10 apolipoproteins in human serum. We optimized sample preparation by depleting the two most abundant serum proteins for improved detectability of low abundant proteins. Intra-day and inter-day imprecision were below 16.5%, demonstrating a high accuracy. In 50 serum samples from participants with either normal weight or obesity, we quantified 8 adipokines and 10 apolipoproteins. Significantly different abundances were observed for five adipokines (adipsin, adiponectin, chemerin, leptin, vaspin) and four apolipoproteins (apo-B100/-C2/-C4/-D) between the body mass index (BMI) groups. Additionally, we applied our MRM assay to serum samples from normal weight children and human adipocyte cell culture supernatants to proof the feasibility for large cohort studies and distinct biological matrices. In summary, this multiplexed assay facilitated the investigation of relationships between adipokines or apolipoproteins and phenotypes or clinical parameters in large cohorts, which may contribute to disease prediction approaches in the future.
Keywords	adipokines ; apolipoproteins ; multiple reaction monitoring ; targeted lc-ms ; obesity ; human serum ; sgbs cells ; cell culture supernatant ; Organic chemistry ; QD241-441
Subject code	616
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Alternatives for the worse

Alexandra Schaffert / Laura Krieg / Juliane Weiner / Rita Schlichting / Elke Ueberham / Isabel Karkossa / Mario Bauer / Kathrin Landgraf / Kristin M. Junge / Martin Wabitsch / Jörg Lehmann / Beate I. Escher / Ana C. Zenclussen / Antje Körner / Matthias Blüher / John T. Heiker / Martin von Bergen / Kristin Schubert

Environment International, Vol 156, Iss , Pp 106730- (2021)

Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation

2021

Abstract: Bisphenol A (BPA), which is used in a variety of consumer-related plastic products, was reported to cause adverse effects, including disruption of adipocyte differentiation, interference with obesity mechanisms, and impairment of insulin- and glucose ... ...

Abstract	Bisphenol A (BPA), which is used in a variety of consumer-related plastic products, was reported to cause adverse effects, including disruption of adipocyte differentiation, interference with obesity mechanisms, and impairment of insulin- and glucose homeostasis. Substitute compounds are increasingly emerging but are not sufficiently investigated. We aimed to investigate the mode of action of BPA and four of its substitutes during the differentiation of human preadipocytes to adipocytes and their molecular interaction with peroxisome proliferator-activated receptor γ (PPARγ), a pivotal regulator of adipogenesis. Binding and effective biological activation of PPARγ were investigated by surface plasmon resonance and reporter gene assay, respectively. Human preadipocytes were continuously exposed to BPA, BPS, BPB, BPF, BPAF, and the PPARγ-antagonist GW9662. After 12 days of differentiation, lipid production was quantified via Oil Red O staining, and global protein profiles were assessed using LC-MS/MS-based proteomics. All tested bisphenols bound to human PPARγ with similar efficacy as the natural ligand 15d-PGJ2 in vitro and provoked an antagonistic effect on PPARγ in the reporter gene assay at non-cytotoxic concentrations. During the differentiation of human preadipocytes, all bisphenols decreased lipid production. Global proteomics displayed a down-regulation of adipogenesis and metabolic pathways, similar to GW9662. Interestingly, pro-inflammatory pathways were up-regulated, MCP1 release was increased, and adiponectin decreased. pAKT/AKT ratios revealed significantly reduced insulin sensitivity by BPA, BPB, and BPS upon insulin stimulation. Thus, our results show that not only BPA but also its substitutes disrupt crucial metabolic functions and insulin signaling in adipocytes under low, environmentally relevant concentrations. This effect, mediated through inhibition of PPARγ, may promote hypertrophy of adipose tissue and increase the risk of developing metabolic syndrome, including insulin resistance.
Keywords	Peroxisome proliferator-activated receptor γ (PPARγ) ; Bisphenol A (BPA) ; Endocrine disruption ; Obesogene ; SGBS ; Proteomics ; Environmental sciences ; GE1-350
Subject code	571
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Concordance of bioactive vs. total immunoreactive serum leptin levels in children with severe early onset obesity.

Juraj Stanik / Jürgen Kratzsch / Kathrin Landgraf / Kathrin Scheuermann / Ulrike Spielau / Ruth Gausche / Daniela Gasperikova / Wieland Kiess / Antje Körner

PLoS ONE, Vol 12, Iss 5, p e

2017 Volume 0178107

Abstract: Leptin secreted from adipose tissue signals peripheral energy status to the brain. Monogenic leptin deficiency results in severe early onset obesity with hyperphagia. Recently, a similar phenotype of inactivating leptin mutations but with preserved ... ...

Abstract	Leptin secreted from adipose tissue signals peripheral energy status to the brain. Monogenic leptin deficiency results in severe early onset obesity with hyperphagia. Recently, a similar phenotype of inactivating leptin mutations but with preserved immunoreactivity and hence normal circulating immunoreactive leptin has been reported.We aimed to evaluate the proportion of bioactive leptin serum levels (compared to immunoreactive leptin) as a biomarker for the screening of leptin gene mutations causing monogenic obesity. Furthermore, we aimed to compare the immunoreactive and bioactive leptin levels associations with parameters of insulin resistance and insulin secretion in obese children and adolescents.We measured bioactive and immunoreactive leptin levels by enzyme-linked immunosorbent assays in fasting serum samples of 70 children with severe (BMI SDS >3) non-syndromic obesity with onset <3 years of life from our Leipzig childhood obesity cohort (n = 1204). Sanger sequencing of the leptin gene was performed in probands with proportion of bioactive/immunoreactive leptin <90%.The mean levels of bioactive and immunoreactive leptin were almost identical (41.1±25.2 vs. 41.1±25.4ng/mL). In three probands with the lowest bioactive leptin proportion (<90%) we did not identify mutations in the leptin gene. Compared to immunoreactive leptin, bioactive leptin showed similar and slightly better statistical associations with indices of insulin resistance in correlation and multivariate analyses.In our sample selected for severe early onset childhood obesity, we did not identify leptin gene mutations leading to decreased proportion of bioactive leptin. Nevertheless, the bioactive leptin levels were stronger associated with selected insulin secretion/resistance indices than the immunoreactive leptin levels.
Keywords	Medicine ; R ; Science ; Q
Subject code	630 ; 616
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: BOR-syndrome-associated Eya1 mutations lead to enhanced proteasomal degradation of Eya1 protein.

Amna Musharraf / Dagmar Kruspe / Jürgen Tomasch / Birgit Besenbeck / Christoph Englert / Kathrin Landgraf

PLoS ONE, Vol 9, Iss 1, p e

2014 Volume 87407

Abstract: Mutations in the human EYA1 gene have been associated with several human diseases including branchio-oto (BO) and branchio-oto-renal (BOR) syndrome, as well as congenital cataracts and ocular anterior segment anomalies. BOR patients suffer from severe ... ...

Abstract	Mutations in the human EYA1 gene have been associated with several human diseases including branchio-oto (BO) and branchio-oto-renal (BOR) syndrome, as well as congenital cataracts and ocular anterior segment anomalies. BOR patients suffer from severe malformations of the ears, branchial arches and kidneys. The phenotype of Eya1-heterozygous mice resembles the symptoms of human patients suffering from BOR syndrome. The Eya1 gene encodes a multifunctional protein that acts as a protein tyrosine phosphatase and a transcriptional coactivator. It has been shown that Eya1 interacts with Six transcription factors, which are also required for nuclear translocation of the Eya1 protein. We investigated the effects of seven disease-causing Eya1 missense mutations on Eya1 protein function, in particular cellular localization, ability to interact with Six proteins, and protein stability. We show here that the BOR-associated Eya1 missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of the Eya1 protein in mammalian cells. Moreover, Six proteins lead to a significant stabilization of Eya1, which is caused by Six-mediated protection from proteasomal degradation. In case of the mutant L550P, loss of interaction with Six proteins leads to rapid protein degradation. Our observations suggest that protein destabilization constitutes a novel disease causing mechanism for Eya1.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG

Kathrin Landgraf / Nora Klöting / Martin Gericke / Nitzan Maixner / Esther Guiu-Jurado / Markus Scholz / A. Veronica Witte / Frauke Beyer / Julian T. Schwartze / Martin Lacher / Arno Villringer / Peter Kovacs / Assaf Rudich / Matthias Blüher / Wieland Kiess / Antje Körner

Cell Reports, Vol 33, Iss 3, Pp 108295- (2020)

2020

Abstract: Summary: 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 ... ...

Abstract	Summary: 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.
Keywords	TMEM18 ; adipose progenitor cells ; adipogenesis ; PPARG ; adipose tissue ; children ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Direct evidence of brown adipocytes in different fat depots in children.

Denise Rockstroh / Kathrin Landgraf / Isabel Viola Wagner / Julia Gesing / Roy Tauscher / Nicole Lakowa / Wieland Kiess / Ulf Bühligen / Magdalena Wojan / Holger Till / Matthias Blüher / Antje Körner

PLoS ONE, Vol 10, Iss 2, p e

2015 Volume 0117841

Abstract: Recent studies suggested the persistence of brown adipocytes in adult humans, as opposed to being exclusively present in infancy. In this study, we investigated the presence of brown-like adipocytes in adipose tissue (AT) samples of children and ... ...

Abstract	Recent studies suggested the persistence of brown adipocytes in adult humans, as opposed to being exclusively present in infancy. In this study, we investigated the presence of brown-like adipocytes in adipose tissue (AT) samples of children and adolescents aged 0 to 18 years and evaluated the association with age, location, and obesity. For this, we analysed AT samples from 131 children and 23 adults by histological, immunohistochemical and expression analyses. We detected brown-like and UCP1 positive adipocytes in 10.3% of 87 lean children (aged 0.3 to 10.7 years) and in one overweight infant, whereas we did not find brown adipocytes in obese children or adults. In our samples, the brown-like adipocytes were interspersed within white AT of perirenal, visceral and also subcutaneous depots. Samples with brown-like adipocytes showed an increased expression of UCP1 (>200fold), PRDM16 (2.8fold), PGC1α and CIDEA while other brown/beige selective markers, such as PAT2, P2RX5, ZIC1, LHX8, TMEM26, HOXC9 and TBX1 were not significantly different between UCP1 positive and negative samples. We identified a positive correlation between UCP1 and PRDM16 within UCP1 positive samples, but not with any other brown/beige marker. In addition, we observed significantly increased PRDM16 and PAT2 expression in subcutaneous and visceral AT samples with high UCP1 expression in adults. Our data indicate that brown-like adipocytes are present well beyond infancy in subcutaneous depots of non-obese children. The presence was not restricted to typical perirenal locations, but they were also interspersed within WAT of visceral and subcutaneous depots.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis

Farnaz Shamsi / Ruidan Xue / Tian Lian Huang / Morten Lundh / Yang Liu / Luiz O. Leiria / Matthew D. Lynes / Elena Kempf / Chih-Hao Wang / Satoru Sugimoto / Pasquale Nigro / Kathrin Landgraf / Tim Schulz / Yiming Li / Brice Emanuelli / Srinivas Kothakota / Lewis T. Williams / Niels Jessen / Steen Bønløkke Pedersen /

Yvonne Böttcher / Matthias Blüher / Antje Körner / Laurie J. Goodyear / Moosa Mohammadi / C. Ronald Kahn / Yu-Hua Tseng

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 16

Abstract: Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue. Here the authors show that FGF6 and FGF9 induce UCP1 expression in adipocytes and preadipocytes, via modulation of a transcriptional network that is ... ...

Abstract	Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue. Here the authors show that FGF6 and FGF9 induce UCP1 expression in adipocytes and preadipocytes, via modulation of a transcriptional network that is dissociated from brown adipogenesis.
Keywords	Science ; Q
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis

Yvonne Böttcher / Matthias Blüher / Antje Körner / Laurie J. Goodyear / Moosa Mohammadi / C. Ronald Kahn / Yu-Hua Tseng

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 16

Abstract	Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue. Here the authors show that FGF6 and FGF9 induce UCP1 expression in adipocytes and preadipocytes, via modulation of a transcriptional network that is dissociated from brown adipogenesis.
Keywords	Science ; Q
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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