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Lecoutre S, Rebière C, Maqdasy S, Lambert M, Dussaud S, Abatan JB, Dugail I, Gautier EL, Clément K, Marcelin G. Enhancing adipose tissue plasticity: progenitor cell roles in metabolic health. Nat Rev Endocrinol 2025; 21:272-288. [PMID: 39757324 DOI: 10.1038/s41574-024-01071-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/27/2024] [Indexed: 01/07/2025]
Abstract
Adipose tissue demonstrates considerable plasticity and heterogeneity, enabling metabolic, cellular and structural adaptations to environmental signals. This adaptability is key for maintaining metabolic homeostasis. Impaired adipose tissue plasticity can lead to abnormal adipose tissue responses to metabolic cues, which contributes to the development of cardiometabolic diseases. In chronic obesity, white adipose tissue undergoes pathological remodelling marked by adipocyte hypertrophy, chronic inflammation and fibrosis, which are linked to local and systemic insulin resistance. Research data suggest that the capacity for healthy or unhealthy white adipose tissue remodelling might depend on the intrinsic diversity of adipose progenitor cells (APCs), which sense and respond to metabolic cues. This Review highlights studies on APCs as key determinants of adipose tissue plasticity, discussing differences between subcutaneous and visceral adipose tissue depots during development, growth and obesity. Modulating APC functions could improve strategies for treating adipose tissue dysfunction and metabolic diseases in obesity.
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Affiliation(s)
- Simon Lecoutre
- Nutrition and Obesities: Systemic Approach Research Group, Nutriomics, Sorbonne Université, INSERM, Paris, France.
| | - Clémentine Rebière
- Nutrition and Obesities: Systemic Approach Research Group, Nutriomics, Sorbonne Université, INSERM, Paris, France
| | - Salwan Maqdasy
- Department of Medicine, Karolinska Institutet Hospital, Stockholm, Sweden
| | - Mélanie Lambert
- Institut National de la Santé et de la Recherche Médicale, Bobigny, France
- Labex Inflamex, Université Sorbonne Paris Nord, Alliance Sorbonne Paris Cité, Bobigny, France
| | - Sébastien Dussaud
- Nutrition and Obesities: Systemic Approach Research Group, Nutriomics, Sorbonne Université, INSERM, Paris, France
| | - Jimon Boniface Abatan
- Nutrition and Obesities: Systemic Approach Research Group, Nutriomics, Sorbonne Université, INSERM, Paris, France
| | - Isabelle Dugail
- Nutrition and Obesities: Systemic Approach Research Group, Nutriomics, Sorbonne Université, INSERM, Paris, France
| | - Emmanuel L Gautier
- Nutrition and Obesities: Systemic Approach Research Group, Nutriomics, Sorbonne Université, INSERM, Paris, France
| | - Karine Clément
- Nutrition and Obesities: Systemic Approach Research Group, Nutriomics, Sorbonne Université, INSERM, Paris, France.
- Department of Nutrition, Pitie-Salpêtriere Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
| | - Geneviève Marcelin
- Nutrition and Obesities: Systemic Approach Research Group, Nutriomics, Sorbonne Université, INSERM, Paris, France.
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2
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Aldehoff AS, Karkossa I, Goerdeler C, Krieg L, Schor J, Engelmann B, Wabitsch M, Landgraf K, Hackermüller J, Körner A, Rolle-Kampczyk U, Schubert K, von Bergen M. Unveiling the dynamics of acetylation and phosphorylation in SGBS and 3T3-L1 adipogenesis. iScience 2024; 27:109711. [PMID: 38840842 PMCID: PMC11152682 DOI: 10.1016/j.isci.2024.109711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/11/2023] [Accepted: 04/06/2024] [Indexed: 06/07/2024] Open
Abstract
Obesity, characterized by enlarged and dysfunctional adipose tissue, is among today's most pressing global public health challenges with continuously increasing prevalence. Despite the importance of post-translational protein modifications (PTMs) in cellular signaling, knowledge of their impact on adipogenesis remains limited. Here, we studied the temporal dynamics of transcriptome, proteome, central carbon metabolites, and the acetyl- and phosphoproteome during adipogenesis using LC-MS/MS combined with PTM enrichment strategies on human (SGBS) and mouse (3T3-L1) adipocyte models. Both cell lines exhibited unique PTM profiles during adipogenesis, with acetylated proteins being enriched for central energy metabolism, while phosphorylated proteins related to insulin signaling and organization of cellular structures. As candidates with strong correlation to the adipogenesis timeline we identified CD44 and the acetylation sites FASN_K673 and IDH_K272. While results generally aligned between SGBS and 3T3-L1 cells, details appeared cell line specific. Our datasets on SGBS and 3T3-L1 adipogenesis dynamics are accessible for further mining.
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Affiliation(s)
- Alix Sarah Aldehoff
- Department of Molecular Toxicology, Helmholtz-Centre for Environmental Research GmbH (UFZ), Leipzig, Germany
| | - Isabel Karkossa
- Department of Molecular Toxicology, Helmholtz-Centre for Environmental Research GmbH (UFZ), Leipzig, Germany
| | - Cornelius Goerdeler
- Department of Molecular Toxicology, Helmholtz-Centre for Environmental Research GmbH (UFZ), Leipzig, Germany
| | - Laura Krieg
- Department of Molecular Toxicology, Helmholtz-Centre for Environmental Research GmbH (UFZ), Leipzig, Germany
| | - Jana Schor
- Department of Computational Biology and Chemistry, Helmholtz-Centre for Environmental Research GmbH (UFZ), Leipzig, Germany
| | - Beatrice Engelmann
- Department of Molecular Toxicology, Helmholtz-Centre for Environmental Research GmbH (UFZ), Leipzig, Germany
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, University Hospital for Children and Adolescents Ulm, Ulm, Germany
| | - Kathrin Landgraf
- University Hospital for Children and Adolescents, Center for Pediatric Research, Medical Faculty, University of Leipzig, Leipzig, Germany
| | - Jörg Hackermüller
- Department of Computational Biology and Chemistry, Helmholtz-Centre for Environmental Research GmbH (UFZ), Leipzig, Germany
- Department of Computer Science, University of Leipzig, Leipzig, Germany
| | - Antje Körner
- University Hospital for Children and Adolescents, Center for Pediatric Research, Medical Faculty, University of Leipzig, Leipzig, Germany
- Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG) of the Helmholtz-Centre Munich at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
- LIFE–Leipzig Research Center for Civilization Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany
| | - Ulrike Rolle-Kampczyk
- Department of Molecular Toxicology, Helmholtz-Centre for Environmental Research GmbH (UFZ), Leipzig, Germany
| | - Kristin Schubert
- Department of Molecular Toxicology, Helmholtz-Centre for Environmental Research GmbH (UFZ), Leipzig, Germany
| | - Martin von Bergen
- Department of Molecular Toxicology, Helmholtz-Centre for Environmental Research GmbH (UFZ), Leipzig, Germany
- Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, University of Leipzig, Leipzig, Germany
- German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany
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Šimon M, Mikec Š, Atanur SS, Konc J, Morton NM, Horvat S, Kunej T. Whole genome sequencing of mouse lines divergently selected for fatness (FLI) and leanness (FHI) revealed several genetic variants as candidates for novel obesity genes. Genes Genomics 2024; 46:557-575. [PMID: 38483771 PMCID: PMC11024027 DOI: 10.1007/s13258-024-01507-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 02/25/2024] [Indexed: 04/18/2024]
Abstract
BACKGROUND Analysing genomes of animal model organisms is widely used for understanding the genetic basis of complex traits and diseases, such as obesity, for which only a few mouse models exist, however, without their lean counterparts. OBJECTIVE To analyse genetic differences in the unique mouse models of polygenic obesity (Fat line) and leanness (Lean line) originating from the same base population and established by divergent selection over more than 60 generations. METHODS Genetic variability was analysed using WGS. Variants were identified with GATK and annotated with Ensembl VEP. g.Profiler, WebGestalt, and KEGG were used for GO and pathway enrichment analysis. miRNA seed regions were obtained with miRPathDB 2.0, LncRRIsearch was used to predict targets of identified lncRNAs, and genes influencing adipose tissue amount were searched using the IMPC database. RESULTS WGS analysis revealed 6.3 million SNPs, 1.3 million were new. Thousands of potentially impactful SNPs were identified, including within 24 genes related to adipose tissue amount. SNP density was highest in pseudogenes and regulatory RNAs. The Lean line carries SNP rs248726381 in the seed region of mmu-miR-3086-3p, which may affect fatty acid metabolism. KEGG analysis showed deleterious missense variants in immune response and diabetes genes, with food perception pathways being most enriched. Gene prioritisation considering SNP GERP scores, variant consequences, and allele comparison with other mouse lines identified seven novel obesity candidate genes: 4930441H08Rik, Aff3, Fam237b, Gm36633, Pced1a, Tecrl, and Zfp536. CONCLUSION WGS revealed many genetic differences between the lines that accumulated over the selection period, including variants with potential negative impacts on gene function. Given the increasing availability of mouse strains and genetic polymorphism catalogues, the study is a valuable resource for researchers to study obesity.
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Affiliation(s)
- Martin Šimon
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia.
| | - Špela Mikec
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia
| | - Santosh S Atanur
- Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, SW7 2AZ, UK
- Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Janez Konc
- Laboratory for Molecular Modeling, National Institute of Chemistry, Ljubljana, 1000, Slovenia
| | - Nicholas M Morton
- The Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Simon Horvat
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia
| | - Tanja Kunej
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia.
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Hagberg CE, Spalding KL. White adipocyte dysfunction and obesity-associated pathologies in humans. Nat Rev Mol Cell Biol 2024; 25:270-289. [PMID: 38086922 DOI: 10.1038/s41580-023-00680-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/13/2023] [Indexed: 02/10/2024]
Abstract
The prevalence of obesity and associated chronic diseases continues to increase worldwide, negatively impacting on societies and economies. Whereas the association between excess body weight and increased risk for developing a multitude of diseases is well established, the initiating mechanisms by which weight gain impairs our metabolic health remain surprisingly contested. In order to better address the myriad of disease states associated with obesity, it is essential to understand adipose tissue dysfunction and develop strategies for reinforcing adipocyte health. In this Review we outline the diverse physiological functions and pathological roles of human white adipocytes, examining our current knowledge of why white adipocytes are vital for systemic metabolic control, yet poorly adapted to our current obesogenic environment.
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Affiliation(s)
- Carolina E Hagberg
- Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Kirsty L Spalding
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
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Amirkhizi F, Khademi Z, Hamedi−Shahraki S, Rahimlou M. Vitamin D insufficiency and its association with adipokines and atherogenic indices in patients with metabolic syndrome: A case-control study. Front Endocrinol (Lausanne) 2023; 14:1080138. [PMID: 36742396 PMCID: PMC9895380 DOI: 10.3389/fendo.2023.1080138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 01/04/2023] [Indexed: 01/22/2023] Open
Abstract
INTRODUCTION Vitamin D deficiency is one of the most common nutritional disorders in most countries of the world. The present study was designed and implemented with the aim of investigating the relationship between vitamin D deficiency and the level of adipokines, atherogenesis indicators and factors related to metabolic syndrome. METHODS This case-control study was done on 195 patients with metabolic syndrome aged 20-50 y who attended the health centers in Zabol County, northeast Iran, between April 2021 and January 2022. Anthropometric and biochemical parameters were measured for all subjects with standard methods. To determine serum 25(OH)D levels, we used enzymatic linked immunosorbent assay (ELISA) kits. Atherogenic index of plasma (AIP) was calculated as log (TG/HDL-c). The visceral adiposity index (VAI) and the lipid accumulation product (LAP) were estimated according to standard formulas. RESULTS AND DISCUSSION Participants in the case group had lower serum levels of 25(OH)D compared to controls (19.8 ± 6.2 ng/ml vs. 41.2 ± 9.7ng/ml, P<0.001). We found that the mean serum levels of fasting blood sugar (P=0.023) and TG (P=0.008) as well as HOMA-IR (P=0.023) were significantly higher in the cases compared to controls. Also, patients with MetS and vitamin D insufficiency (cases) had higher AIP (P=0.040) and LAP (P=0.012) than controls. Furthermore, serum 25(OH)D levels showed significant inverse correlations with serum RBP-4 and a positive correlation with serum omentin-1 concentrations. The results of the present study showed that vitamin D deficiency correlated with some of the cardiometabolic risk factors among the patients with MetS.
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Affiliation(s)
- Farshad Amirkhizi
- Department of Nutrition, Faculty of Public Health, Zabol University of Medical Sciences, Zabol, Iran
| | - Zeinab Khademi
- Department of Public Health, Sirjan School of Medical Sciences, Sirjan, Iran
| | - Soudabeh Hamedi−Shahraki
- Department of Epidemiology and Biostatistics, Faculty of Public Health, Zabol University of Medical Sciences, Zabol, Iran
| | - Mehran Rahimlou
- Department of Nutrition, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
- *Correspondence: Mehran Rahimlou,
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Zhang R, Xu J, Li R, Yu Z, Yuan W, Gao H, Feng W, Gu C, Sun Z, Zheng L. Association between Serum Spermidine and TyG Index: Results from a Cross-Sectional Study. Nutrients 2022; 14:nu14183847. [PMID: 36145224 PMCID: PMC9500746 DOI: 10.3390/nu14183847] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 12/30/2022] Open
Abstract
Background: Although animal experiments have shown that spermidine (SPD) affects insulin resistance (IR), the evidence for this in humans is still scarce. We aimed to investigate the associations between serum SPD levels and the TyG index in the adult population. Methods: A cross-sectional study was carried out with 4336 participants, all of whom were adults aged 35+ years. The SPD levels in serum were detected using high performance liquid chromatography with a fluorescence detector (HPLC-FLD). The triglyceride-glucose (TyG) index was calculated as Ln [fasting triglycerides (TG) (mg/dL) × fasting glucose (mg/dL)/2]. Results: After multivariable adjustment, including demographic characteristics, behavioral factors associated with heath, and a history of taking medicine, SPD was inversely associated with the TyG index (β = −0.036; SE: 0.009; p < 0.001). Furthermore, each increase of 1 lnSPD significantly decreased the risk of IR with an odds ratio (ORs) (95% confidence intervals (CIs)) of 0.89 (0.83−0.96). Relative to the first quintile, the multivariate-adjusted ORs (95% CIs) for the third and fourth quartile group were 0.80 (0.65, 0.99) and 0.71 (0.57, 0.88), respectively. Conclusions: In conclusion, SPD was inversely associated with the TyG index. Our findings inform future exploratory research on the further mechanism of the association between spermidine and IR.
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Affiliation(s)
- Rui Zhang
- College of Public Health, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
- Correspondence: (R.Z.); (L.Z.); Tel./Fax: +86-21-65881635 (R.Z.); +86-21-63846590 (L.Z.)
| | - Jiahui Xu
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, 227 Chongqing South Road, Huangpu District, Shanghai 200025, China
- Infectious Disease Prevention and Control Center, Hohhot Center for Disease Control and Prevention, Hohhot 010070, China
| | - Ruixue Li
- School of Public Health, China Medical University, Shenyang 110122, China
| | - Zhecong Yu
- School of Public Health, China Medical University, Shenyang 110122, China
| | - Wei Yuan
- School of Public Health, China Medical University, Shenyang 110122, China
| | - Hanshu Gao
- School of Public Health, China Medical University, Shenyang 110122, China
| | - Wenjing Feng
- School of Public Health, China Medical University, Shenyang 110122, China
| | - Cuiying Gu
- School of Public Health, China Medical University, Shenyang 110122, China
| | - Zhaoqing Sun
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Liqiang Zheng
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, 227 Chongqing South Road, Huangpu District, Shanghai 200025, China
- Correspondence: (R.Z.); (L.Z.); Tel./Fax: +86-21-65881635 (R.Z.); +86-21-63846590 (L.Z.)
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Chen Y, Li EM, Xu LY. Guide to Metabolomics Analysis: A Bioinformatics Workflow. Metabolites 2022; 12:357. [PMID: 35448542 PMCID: PMC9032224 DOI: 10.3390/metabo12040357] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/12/2022] [Accepted: 04/14/2022] [Indexed: 02/05/2023] Open
Abstract
Metabolomics is an emerging field that quantifies numerous metabolites systematically. The key purpose of metabolomics is to identify the metabolites corresponding to each biological phenotype, and then provide an analysis of the mechanisms involved. Although metabolomics is important to understand the involved biological phenomena, the approach's ability to obtain an exhaustive description of the processes is limited. Thus, an analysis-integrated metabolomics, transcriptomics, proteomics, and other omics approach is recommended. Such integration of different omics data requires specialized statistical and bioinformatics software. This review focuses on the steps involved in metabolomics research and summarizes several main tools for metabolomics analyses. We also outline the most abnormal metabolic pathways in several cancers and diseases, and discuss the importance of multi-omics integration algorithms. Overall, our goal is to summarize the current metabolomics analysis workflow and its main analysis software to provide useful insights for researchers to establish a preferable pipeline of metabolomics or multi-omics analysis.
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Affiliation(s)
- Yang Chen
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China
| | - Li-Yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041,
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Piras C, Noto A, Ibba L, Deidda M, Fanos V, Muntoni S, Leoni VP, Atzori L. Contribution of Metabolomics to the Understanding of NAFLD and NASH Syndromes: A Systematic Review. Metabolites 2021; 11:metabo11100694. [PMID: 34677409 PMCID: PMC8541039 DOI: 10.3390/metabo11100694] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/03/2021] [Accepted: 10/06/2021] [Indexed: 12/20/2022] Open
Abstract
Several differential panels of metabolites have been associated with the presence of metabolic syndrome and its related conditions, namely non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). This study aimed to perform a systematic review to summarize the most recent finding in terms of circulating biomarkers following NAFLD/NASH syndromes. Hence, the research was focused on NAFLD/NASH studies analysed by metabolomics approaches. Following Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, a systematic search was conducted on the PubMed database. The inclusion criteria were (i) publication date between 2010 and 2021, (ii) presence of the combination of terms: metabolomics and NAFLD/NASH, and (iii) published in a scholarly peer-reviewed journal. Studies were excluded from the review if they were (i) single-case studies, (ii) unpublished thesis and dissertation studies, and (iii) not published in a peer-reviewed journal. Following these procedures, 10 eligible studies among 93 were taken into consideration. The metabolisms of amino acids, fatty acid, and vitamins were significantly different in patients affected by NAFLD and NASH compared to healthy controls. These findings suggest that low weight metabolites are an important indicator for NAFLD/NASH syndrome and there is a strong overlap between NAFLD/NASH and the metabolic syndrome. These findings may lead to new perspectives in early diagnosis, identification of novel biomarkers, and providing novel targets for pharmacological interventions.
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Affiliation(s)
- Cristina Piras
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
| | - Antonio Noto
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
- Correspondence:
| | - Luciano Ibba
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
| | - Martino Deidda
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy;
| | - Vassilios Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, University of Cagliari, 09042 Monserrato, Italy;
| | - Sandro Muntoni
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
| | - Vera Piera Leoni
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
| | - Luigi Atzori
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
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9
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Morais T, Seabra AL, Patrício BG, Guimarães M, Nora M, Oliveira PF, Alves MG, Monteiro MP. Visceral Adipose Tissue Displays Unique Metabolomic Fingerprints in Obesity, Pre-Diabetes and Type 2 Diabetes. Int J Mol Sci 2021; 22:5695. [PMID: 34071774 PMCID: PMC8199212 DOI: 10.3390/ijms22115695] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/24/2021] [Accepted: 05/24/2021] [Indexed: 11/16/2022] Open
Abstract
Visceral adipose tissue (VAT) metabolic profiling harbors the potential to disentangle molecular changes underlying obesity-related dysglycemia. In this study, the VAT exometabolome of subjects with obesity and different glycemic statuses are analyzed. The subjects (n = 19) are divided into groups according to body mass index and glycemic status: subjects with obesity and euglycemia (Ob+NGT, n = 5), subjects with obesity and pre-diabetes (Ob+Pre-T2D, n = 5), subjects with obesity and type 2 diabetes under metformin treatment (Ob+T2D, n = 5) and subjects without obesity and with euglycemia (Non-Ob, n = 4), used as controls. VATs are incubated in culture media and extracellular metabolite content is determined by proton nuclear magnetic resonance (1H-NMR). Glucose consumption is not different between the groups. Pyruvate and pyroglutamate consumption are significantly lower in all groups of subjects with obesity compared to Non-Ob, and significantly lower in Ob+Pre-T2D as compared to Ob+NGT. In contrast, isoleucine consumption is significantly higher in all groups of subjects with obesity, particularly in Ob+Pre-T2D, compared to Non-Ob. Acetate production is also significantly lower in Ob+Pre-T2D compared to Non-Ob. In sum, the VAT metabolic fingerprint is associated with pre-diabetes and characterized by higher isoleucine consumption, accompanied by lower acetate production and pyruvate and pyroglutamate consumption. We propose that glucose metabolism follows different fates within the VAT, depending on the individuals' health status.
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Affiliation(s)
- Tiago Morais
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal; (T.M.); (A.L.S.); (B.G.P.); (M.G.); (M.N.); (M.G.A.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4050-313 Porto, Portugal
- Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
| | - Alexandre L. Seabra
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal; (T.M.); (A.L.S.); (B.G.P.); (M.G.); (M.N.); (M.G.A.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4050-313 Porto, Portugal
- Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
| | - Bárbara G. Patrício
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal; (T.M.); (A.L.S.); (B.G.P.); (M.G.); (M.N.); (M.G.A.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4050-313 Porto, Portugal
- Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
| | - Marta Guimarães
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal; (T.M.); (A.L.S.); (B.G.P.); (M.G.); (M.N.); (M.G.A.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4050-313 Porto, Portugal
- Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
- Department of General Surgery, Centro Hospitalar de Entre o Douro e Vouga, 4520-220 Santa Maria da Feira, Portugal
| | - Mário Nora
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal; (T.M.); (A.L.S.); (B.G.P.); (M.G.); (M.N.); (M.G.A.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4050-313 Porto, Portugal
- Department of General Surgery, Centro Hospitalar de Entre o Douro e Vouga, 4520-220 Santa Maria da Feira, Portugal
| | - Pedro F. Oliveira
- QOPNA & LAQV, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - Marco G. Alves
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal; (T.M.); (A.L.S.); (B.G.P.); (M.G.); (M.N.); (M.G.A.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4050-313 Porto, Portugal
- Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
| | - Mariana P. Monteiro
- Endocrine and Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal; (T.M.); (A.L.S.); (B.G.P.); (M.G.); (M.N.); (M.G.A.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4050-313 Porto, Portugal
- Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
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10
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Paczkowska-Abdulsalam M, Kretowski A. Obesity, metabolic health and omics: Current status and future directions. World J Diabetes 2021; 12:420-436. [PMID: 33889288 PMCID: PMC8040086 DOI: 10.4239/wjd.v12.i4.420] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/22/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023] Open
Abstract
The growing obesity epidemic is becoming a major public health concern, and the associated costs represent a considerable burden on societies. Among the most common complications of severe obesity are the development of hypertension, dyslipidemia, type 2 diabetes, cardiovascular disease, and various types of cancer. Interestingly, some obese individuals have a favorable metabolic profile and appear to be somehow protected from the detrimental effects of excessive adipose tissue accumulation. These individuals remain normoglycemic, insulin sensitive, and hypotensive with proper blood lipid levels, despite their high body mass index and/or waist circumference. Multiple independent observations have led to the concept of the metabolically healthy obese (MHO) phenotype, yet no consensus has been reached to date regarding a universal definition or the main mechanism behind this phenomenon. Recent technological advances and the use of high-throughput analysis techniques have revolutionized different areas of biomedical research. A multi-omics approach, which is used to investigate changes at different molecular levels in an organism or tissue, may provide valuable insights into the interplay between the molecules or pathways and the roles of different factors involved in the mechanisms underlying metabolic health deterioration. The aim of this review is to present the current status regarding the use of omics technologies to investigate the MHO phenotype, as well as the results of targeted analyses conducted in MHO individuals.
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Affiliation(s)
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, Bialystok 15-276, Poland
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok 15-276, Poland
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11
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Barroso Oquendo M, Siegel-Axel D, Gerst F, Lorza-Gil E, Moller A, Wagner R, Machann J, Fend F, Königsrainer A, Heni M, Häring HU, Ullrich S, Birkenfeld AL. Pancreatic fat cells of humans with type 2 diabetes display reduced adipogenic and lipolytic activity. Am J Physiol Cell Physiol 2021; 320:C1000-C1012. [PMID: 33788629 DOI: 10.1152/ajpcell.00595.2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Obesity, especially visceral fat accumulation, increases the risk of type 2 diabetes (T2D). The purpose of this study was to investigate the impact of T2D on the pancreatic fat depot. Pancreatic fat pads from 17 partial pancreatectomized patients (PPP) were collected, pancreatic preadipocytes isolated, and in vitro differentiated. Patients were grouped using HbA1c into normal glucose tolerant (NGT), prediabetic (PD), and T2D. Transcriptome profiles of preadipocytes and adipocytes were assessed by RNAseq. Insulin sensitivity was estimated by quantifying AKT phosphorylation on Western blots. Lipogenic capacity was assessed with oil red O staining, lipolytic activity via fatty acid release. Secreted factors were measured using ELISA. Comparative transcriptome analysis of preadipocytes and adipocytes indicates defective upregulation of genes governing adipogenesis (NR1H3), lipogenesis (FASN, SCD, ELOVL6, and FADS1), and lipolysis (LIPE) during differentiation of cells from T2D-PPP. In addition, the ratio of leptin/adiponectin mRNA was higher in T2D than in NGT-PPP. Preadipocytes and adipocytes of NGT-PPP were more insulin sensitive than T2D-PPP cells in regard to AKT phosphorylation. Triglyceride accumulation was similar in NGT and T2D adipocytes. Despite a high expression of the receptors NPR1 and NPR2 in NGT and T2D adipocytes, lipolysis was stimulated by ANP 1.74-fold in NGT cells only. This stimulation was further increased by the PDE5 inhibitor dipyridamole (3.09-fold). Dipyridamole and forskolin increased lipolysis receptor independently 1.88-fold and 1.48-fold, respectively, solely in NGT cells. In conclusion, the metabolic status persistently affects differentiation and lipolysis of pancreatic adipocytes. These alterations could aggravate the development of T2D.
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Affiliation(s)
- Morgana Barroso Oquendo
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Dorothea Siegel-Axel
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Felicia Gerst
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls-University of Tübingen, Neuherberg, Germany.,Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Estela Lorza-Gil
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls-University of Tübingen, Neuherberg, Germany.,Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Anja Moller
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls-University of Tübingen, Neuherberg, Germany.,Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Robert Wagner
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls-University of Tübingen, Neuherberg, Germany.,Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Jürgen Machann
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls-University of Tübingen, Neuherberg, Germany.,Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Falko Fend
- Institute of Pathology and Neuropathology, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Alfred Königsrainer
- Department of General, Visceral and Transplant Surgery, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Martin Heni
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls-University of Tübingen, Neuherberg, Germany.,Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany.,Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls-University of Tübingen, Neuherberg, Germany.,Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Susanne Ullrich
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls-University of Tübingen, Neuherberg, Germany.,Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Andreas L Birkenfeld
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls-University of Tübingen, Neuherberg, Germany.,Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine IV, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany
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12
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Cheng D, Zhao X, Yang S, Cui H, Wang G. Metabolomic Signature Between Metabolically Healthy Overweight/Obese and Metabolically Unhealthy Overweight/Obese: A Systematic Review. Diabetes Metab Syndr Obes 2021; 14:991-1010. [PMID: 33692630 PMCID: PMC7939496 DOI: 10.2147/dmso.s294894] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/28/2021] [Indexed: 12/11/2022] Open
Abstract
The clinical manifestations of overweight/obesity are heterogeneous and complex. In contrast to metabolically unhealthy overweight/obese (MUO), a particular sub-group of obese patients who are considered as metabolically healthy overweight/obese (MHO), display favorable metabolic profiles characterized by high levels of insulin sensitivity, normal blood pressure, as well as favorable lipid, inflammation, hormone, liver enzyme, and immune profiles. While only a few available studies focused on the metabolic files underlying the obese phenotypes, the current review aimed to perform a systematic review of available studies focusing on describing the metabolomic signature between MUO and MHO. We did the systematic search for literature on MEDLINE (PubMed), the Cochrane Library, EMBASE, and searched for the references of relevant manuscripts from inception to 29 May 2020. After critical selection, 20 studies were eligible for this systematic review and evaluated by using QUADOMICS for quality assessment. Eventually, 12 of 20 studies were classified as "high quality". Branched-chain amino acids (isoleucine, leucine, and valine), aromatic amino acids (phenylalanine and tyrosine), lipids (palmitic acid, palmitoleic acid, oleic acid, eicosapentaenoic acid, and docosahexaenoic acid), and acylcarnitines (propionyl carnitine) levels might be elevated in MUO. The current results suggested that MHO showed a favorable trend in the overall metabolic signature. More longitudinal studies are needed to elaborate deeply on the metabolic pathway and the relationship between metabolic patterns and the occurrence of the disease.
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Affiliation(s)
- Dihe Cheng
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China
| | - Xue Zhao
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China
| | - Shuo Yang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China
| | - Haiying Cui
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China
| | - Guixia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China
- Correspondence: Guixia Wang Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of ChinaTel +15843081103 Email
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13
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Healthy Obese Subjects Differ in Chronotype, Sleep Habits, and Adipose Tissue Fatty Acid Composition from Their Non-Healthy Counterparts. Nutrients 2020; 13:nu13010119. [PMID: 33396200 PMCID: PMC7824395 DOI: 10.3390/nu13010119] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/22/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Obesity is not the same in all individuals and two different phenotypes have been described: metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). The aim of this study was to identify factors that explain metabolic health status in a rigorously matched Spanish population. Subcutaneous and visceral fat, adipocyte size and fatty acid composition, cardiometabolic markers in serum, and lifestyle habits were assessed. Higher physical activity in the mornings (Odds Ratio (95% Confidence Interval) (OR (95% CI) = 1.54 (1.09–2.18), p = 0.01)), earlier bedtimes (8:30–10:30 pm) (OR = 2.11 (1.02–4.36), p = 0.04), a complete breakfast (OR = 1.59 (1.07–2.36), p = 0.02), and a greater number of meals per day (4.10 ± 0.05 vs. 3.93 ± 0.05, p < 0.01), were associated with the MHO phenotype. Concentrations of 20:5 n-3 eicosapentaenoic acid (0.26 ± 0.46 vs. 0.10% ± 0.11%, p = 0.04) and 18:3 n-6 gamma-linolenic acid (0.37 ± 0.24 vs. 0.23% ± 0.22%, p = 0.04) in subcutaneous adipocytes were higher and omental adipocyte size (187 094 ± 224 059 µm3 vs. 490 953 ± 229 049 µm3, p = 0.02) was lower in MHO subjects than in those with MUO. Visceral fat area differed between MHO and MUO subjects (135 ± 60 cm2 vs. 178 ± 85 cm2, p = 0.04, respectively). The study highlights specific lifestyle habits that could form part of obesity therapies, not only involving healthier eating habits but also earlier sleeping and exercise patterns.
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14
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Increased mitochondrial respiration of adipocytes from metabolically unhealthy obese compared to healthy obese individuals. Sci Rep 2020; 10:12407. [PMID: 32709986 PMCID: PMC7382448 DOI: 10.1038/s41598-020-69016-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 06/30/2020] [Indexed: 02/07/2023] Open
Abstract
Among obese subjects, metabolically healthy (MHO) and unhealthy obese (MUHO) subjects exist, the latter being characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Insulin resistance and obesity are known to associate with alterations in mitochondrial density, morphology, and function. Therefore, we assessed mitochondrial function in human subcutaneous preadipocytes as well as in differentiated adipocytes derived from well-matched donors. Primary subcutaneous preadipocytes from 4 insulin-resistant (MUHO) versus 4 insulin-sensitive (MHO), non-diabetic, morbidly obese Caucasians (BMI > 40 kg/m2), matched for sex, age, BMI, and percentage of body fat, were differentiated in vitro to adipocytes. Real-time cellular respiration was measured using an XF24 Extracellular Flux Analyzer (Seahorse). Lipolysis was stimulated by forskolin (FSK) treatment. Mitochondrial respiration was fourfold higher in adipocytes versus preadipocytes (p = 1.6*10–9). In adipocytes, a negative correlation of mitochondrial respiration with donors’ insulin sensitivity was shown (p = 0.0008). Correspondingly, in adipocytes of MUHO subjects, an increased basal respiration (p = 0.002), higher proton leak (p = 0.04), elevated ATP production (p = 0.01), increased maximal respiration (p = 0.02), and higher spare respiratory capacity (p = 0.03) were found, compared to MHO. After stimulation with FSK, the differences in ATP production, maximal respiration and spare respiratory capacity were blunted. The differences in mitochondrial respiration between MUHO/MHO were not due to altered mitochondrial content, fuel switch, or lipid metabolism. Thus, despite the insulin resistance of MUHO, we could clearly show an elevated mitochondrial respiration of MUHO adipocytes. We suggest that the higher mitochondrial respiration reflects a compensatory mechanism to cope with insulin resistance and its consequences. Preserving this state of compensation might be an attractive goal for preventing or delaying the transition from insulin resistance to overt diabetes.
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15
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Fibroblast Growth Factor 21 Is Elevated in HIV and Associated With Interleukin-6. J Acquir Immune Defic Syndr 2020; 83:e30-e33. [PMID: 31913998 DOI: 10.1097/qai.0000000000002285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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16
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Ocaña-Wilhelmi L, Cardona F, Garrido-Sanchez L, Fernandez-Garcia D, Tinahones FJ, Ramos-Molina B. Change in serum polyamine metabolome pattern after bariatric surgery in obese patients with metabolic syndrome. Surg Obes Relat Dis 2019; 16:306-311. [PMID: 31813775 DOI: 10.1016/j.soard.2019.10.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Recent works have reported that bariatric surgery has remarkable effects on the metabolome, which might be potentially associated to the metabolic improvement of this procedure in patients with obesity. Serum polyamines, metabolites derived from amino acid metabolism, have been recently related to the metabolic status in obese individuals. However, the impact of bariatric surgery on the circulating levels of polyamines remains elusive. OBJECTIVE To evaluate the effect of bariatric surgery on serum polyamine levels and to evaluate the association of changes in these molecules with metabolic improvement in patients with morbid obesity. SETTING Virgen de la Victoria University Hospital, Malaga, Spain. METHODS This study included 32 morbidly obese patients (weight index ≥40 kg/m2) with metabolic syndrome, who underwent sleeve gastrectomy. Serum levels of polyamines (putrescine, spermidine, and spermine), acetylpolyamines, and polyamine-related amino acids (arginine and ornithine) were assessed at baseline and 6 months after bariatric surgery, and were analyzed in an ultraperformance liquid chromatography-mass spectrometry platform. RESULTS Our metabolomic analysis revealed a significant rise in several metabolites related to the polyamine metabolism, such as putrescine and acetyl derivatives of spermidine and spermine in serum samples from morbidly obese patients after bariatric surgery. Changes in serum levels of both putrescine and acetylputrescine were associated to the resolution of metabolic syndrome after surgery. CONCLUSION Our study indicates that bariatric surgery affects the serum polyamine pattern and the resolution of metabolic syndrome after bariatric surgery is associated to specific changes in the serum polyamine metabolome.
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Affiliation(s)
- Luis Ocaña-Wilhelmi
- Unidad de Cirugía Metabólica, Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - Fernando Cardona
- Unidad Gestión Clínica Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain
| | - Lourdes Garrido-Sanchez
- Unidad Gestión Clínica Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain
| | - Diego Fernandez-Garcia
- Unidad Gestión Clínica Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - Francisco J Tinahones
- Unidad Gestión Clínica Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain.
| | - Bruno Ramos-Molina
- Unidad Gestión Clínica Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain
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17
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Keuper M, Häring HU, Staiger H. Circulating FGF21 Levels in Human Health and Metabolic Disease. Exp Clin Endocrinol Diabetes 2019; 128:752-770. [PMID: 31108554 DOI: 10.1055/a-0879-2968] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Human fibroblast growth factor 21 (FGF21) is primarily produced and secreted by the liver as a hepatokine. This hormone circulates to its target tissues (e. g., brain, adipose tissue), which requires two components, one of the preferred FGF receptor isoforms (FGFR1c and FGFR3c) and the co-factor beta-Klotho (KLB) to trigger downstream signaling pathways. Although targeting FGF21 signaling in humans by analogues and receptor agonists results in beneficial effects, e. g., improvements in plasma lipids and decreased body weight, it failed to recapitulate the improvements in glucose handling shown for many mouse models. FGF21's role and metabolic effects in mice and its therapeutic potential have extensively been reviewed elsewhere. In this review we focus on circulating FGF21 levels in humans and their associations with disease and clinical parameters, focusing primarily on obesity and obesity-associated diseases such as type-2 diabetes. We provide a comprehensive overview on human circulating FGF21 levels under normal physiology and metabolic disease. We discuss the emerging field of inactivating FGF21 in human blood by fibroblast activation protein (FAP) and its potential clinical implications.
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Affiliation(s)
- Michaela Keuper
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany.,Department of Molecular Bioscience, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany.,Interfaculty Centre for Pharmacogenomics and Pharma Research at the Eberhard Karls University Tübingen, Tübingen, Germany.,Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany.,Interfaculty Centre for Pharmacogenomics and Pharma Research at the Eberhard Karls University Tübingen, Tübingen, Germany.,Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, Tübingen, Germany
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18
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Keuper M, Berti L, Raedle B, Sachs S, Böhm A, Fritsche L, Fritsche A, Häring HU, Hrabě de Angelis M, Jastroch M, Hofmann SM, Staiger H. Preadipocytes of obese humans display gender-specific bioenergetic responses to glucose and insulin. Mol Metab 2019; 20:28-37. [PMID: 30528280 PMCID: PMC6358537 DOI: 10.1016/j.molmet.2018.11.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/14/2018] [Accepted: 11/21/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND/OBJECTIVES Although the prevalence of obesity and its associated metabolic disorders is increasing in both sexes, the clinical phenotype differs between men and women, highlighting the need for individual treatment options. Mitochondrial dysfunction in various tissues, including white adipose tissue (WAT), has been accepted as a key factor for obesity-associated comorbidities such as diabetes. Given higher expression of mitochondria-related genes in the WAT of women, we hypothesized that gender differences in the bioenergetic profile of white (pre-) adipocytes from obese (age- and BMI-matched) donors must exist. SUBJECTS/METHODS Using Seahorse technology, we measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) of (pre-)adipocytes from male (n = 10) and female (n = 10) deeply-phenotyped obese donors under hypo-, normo- and hyperglycemic (0, 5 and 25 mM glucose) and insulin-stimulated conditions. Additionally, expression levels (mRNA/protein) of mitochondria-related genes (e.g. UQCRC2) and glycolytic enzymes (e.g. PKM2) were determined. RESULTS Dissecting cellular OCR and ECAR into different functional modules revealed that preadipocytes from female donors show significantly higher mitochondrial to glycolytic activity (higher OCR/ECAR ratio, p = 0.036), which is supported by a higher ratio of UQCRC2 to PKM2 mRNA levels (p = 0.021). However, no major gender differences are detectable in in vitro differentiated adipocytes (e.g. OCR/ECAR, p = 0.248). Importantly, glucose and insulin suppress mitochondrial activity (i.e. ATP-linked respiration) significantly only in preadipocytes of female donors, reflecting their trends towards higher insulin sensitivity. CONCLUSIONS Collectively, we show that preadipocytes, but not in vitro differentiated adipocytes, represent a model system to reveal gender differences with clinical importance for metabolic disease status. In particular preadipocytes of females maintain enhanced mitochondrial flexibility, as demonstrated by pronounced responses of ATP-linked respiration to glucose.
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Affiliation(s)
- Michaela Keuper
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
| | - Lucia Berti
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Bernhard Raedle
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Stephan Sachs
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Diabetes and Regeneration Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Anja Böhm
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Louise Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany
| | - Martin Hrabě de Angelis
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany
| | - Martin Jastroch
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Susanna M Hofmann
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Diabetes and Regeneration Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; Medizinische Klinik und Poliklinik IV Klinikum der LMU München, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, Tübingen, Germany
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Fernandez-Garcia JC, Delpino-Rius A, Samarra I, Castellano-Castillo D, Muñoz-Garach A, Bernal-Lopez MR, Queipo-Ortuño MI, Cardona F, Ramos-Molina B, Tinahones FJ. Type 2 Diabetes Is Associated with a Different Pattern of Serum Polyamines: A Case⁻Control Study from the PREDIMED-Plus Trial. J Clin Med 2019; 8:jcm8010071. [PMID: 30634588 PMCID: PMC6352090 DOI: 10.3390/jcm8010071] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/05/2019] [Accepted: 01/07/2019] [Indexed: 12/20/2022] Open
Abstract
Objective: Polyamines are naturally occurring cationic molecules present in all living cells. Dysregulation of circulating polyamines has been reported in several conditions, but little is known about the levels of serum polyamines in chronic metabolic disorders such as type 2 diabetes (T2D). Therefore, the aim of this study was to evaluate the polyamine-related metabolome in a cohort of metabolic syndrome individuals with and without T2D. Design and methods: This was a nested case–control study within the PREDIMED-Plus trial that included 44 patients with T2D and 70 patients without T2D. We measured serum levels of arginine, ornithine, polyamines, and acetyl polyamines with an ultra-high performance liquid chromatography tandem mass spectrometry platform. Results: Our results showed that serum putrescine, directly generated from ornithine by the catalytic action of the biosynthetic enzyme ornithine decarboxylase, was significantly elevated in patients with T2D compared to those without T2D, and that it significantly correlated with the levels of glycosylated hemoglobin (HbA1c). Correlation analysis revealed a significantly positive association between fasting insulin levels and spermine. Multiple logistic regression analysis (adjusted for age, gender and body weight index) revealed that serum putrescine and spermine levels were associated with a higher risk of T2D. Conclusions: Our study suggests that polyamine metabolism is dysregulated in T2D, and that serum levels of putrescine and spermine are associated with glycemic control and circulating insulin levels, respectively.
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Affiliation(s)
- Jose C Fernandez-Garcia
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Malaga 29010, Spain.
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III, Madrid 28029, Spain.
| | - Antoni Delpino-Rius
- Eurecat, Centre Tecnològic de Catalunya, Centre for Omic Sciences (Joint Unit Eurecat-Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Reus 43204, Spain.
| | - Iris Samarra
- Eurecat, Centre Tecnològic de Catalunya, Centre for Omic Sciences (Joint Unit Eurecat-Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Reus 43204, Spain.
| | - Daniel Castellano-Castillo
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Malaga 29010, Spain.
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III, Madrid 28029, Spain.
| | - Araceli Muñoz-Garach
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Malaga 29010, Spain.
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III, Madrid 28029, Spain.
| | - Maria R Bernal-Lopez
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III, Madrid 28029, Spain.
- Department of Internal Medicine, Regional University Hospital of Malaga, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga 29010, Spain.
| | - Maria I Queipo-Ortuño
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Malaga 29010, Spain.
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III, Madrid 28029, Spain.
- Department of Medical Oncology, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Malaga 29010, Spain.
| | - Fernando Cardona
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Malaga 29010, Spain.
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III, Madrid 28029, Spain.
| | - Bruno Ramos-Molina
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Malaga 29010, Spain.
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III, Madrid 28029, Spain.
| | - Francisco J Tinahones
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Malaga 29010, Spain.
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III, Madrid 28029, Spain.
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20
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Yang C, Wong CM, Wei J, Chung ACK, Cai Z. The brominated flame retardant BDE 47 upregulates purine metabolism and mitochondrial respiration to promote adipocyte differentiation. THE SCIENCE OF THE TOTAL ENVIRONMENT 2018; 644:1312-1322. [PMID: 30743844 DOI: 10.1016/j.scitotenv.2018.07.087] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 07/04/2018] [Accepted: 07/07/2018] [Indexed: 06/09/2023]
Abstract
Adipocyte differentiation is closely associated with obesity and obesity-induced metabolic disorders. Epidemiological studies have demonstrated the association of obesity with environmental pollutants, such as polybrominated diphenyl ethers (PBDEs), common flame retardants in various consumer products. However, their obesogenic effects and mechanism are underexplored. We employed non-targeted metabolomics studies based on liquid chromatography-high resolution mass spectrometry to determine how 2,2',4,4'-tetra-brominated biphenyl ether (BDE 47), one of the main congeners of PBDEs detected in human tissue, promotes adipocyte differentiation of mouse preadipocyte 3 T3-L1 cells. The promoting effects of BDE 47 exposure (5 or 10 μM) on adipocyte differentiation were confirmed by enhancing lipid accumulation and expression levels of biomarkers of adipogenesis. For the first time, we demonstrated that BDE 47 upregulated purine metabolism and altered glutathione metabolism to promote oxidative stress and uric acid production in adipocytes. BDE 47 also elevated mitochondrial respiration and glycolysis in adipocytes to induce more ATP to combat oxidative stress. Antioxidant treatments, including the suppression of xanthine oxidase, inhibited the effects of BDE 47 on inducing oxidative stress and lipid accumulation. BDE 47 may be a potential environmental obesogen by providing a permissive oxidative environment to induce adipocyte differentiation.
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Affiliation(s)
- Chunxue Yang
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
| | - Chi-Ming Wong
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
| | - Juntong Wei
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
| | - Arthur C K Chung
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China; HKBU Institute for Research and Continuing Education, Shenzhen, China.
| | - Zongwei Cai
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China; HKBU Institute for Research and Continuing Education, Shenzhen, China.
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21
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Nam KH, Yun HR, Joo YS, Kim J, Lee S, Lee C, Park KS, Park JT, Chang TI, Kang EW, Yoo TH, Kang SW, Han SH. Changes in obese metabolic phenotypes over time and risk of incident chronic kidney disease. Diabetes Obes Metab 2018; 20:2778-2791. [PMID: 29971899 DOI: 10.1111/dom.13458] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 06/27/2018] [Accepted: 06/29/2018] [Indexed: 12/20/2022]
Abstract
AIM To examine the association between metabolically healthy obese (MHO) phenotype and incident chronic kidney disease (CKD) and study whether changes in metabolic phenotypes over time could affect CKD risk. METHODS A total of 8589 subjects from the Korean Genome and Epidemiology Study were categorized into four groups based on the presence of obesity and metabolic abnormalities (MA). The primary endpoint was an onset of incident CKD defined as an estimated glomerular filtration rate of ≤ 60 mL/min/1.73 m2 . Multivariable Cox analysis and time-varying Cox analysis were performed to delineate the relationship between obese metabolic phenotypes and incident CKD after adjustment for sociodemographic factors and clinical and laboratory parameters. RESULTS During a mean follow-up duration of 9.3 years, CKD occurred in 782 (9.1%) participants. In the multivariable Cox model, the hazard ratio (HR) for incident CKD in the MHO, metabolically abnormal non-obese (MANO), and metabolically abnormal obese (MAO) groups was 1.42 (P = 0.002), 1.45 (P < 0.001), and 1.77 (P < 0.001), respectively, compared with the metabolically healthy non-obese (MHNO) group. Time-varying analysis with these four phenotypes as time-varying exposures showed the same results. Furthermore, subjects with persistent MHO through follow-up were at a 2.0-fold increased risk of CKD (P < 0.001). 41.0% of subjects experienced phenotype changes during follow-up. Over the long term, the MHO group had a higher proportion of transition to the MA phenotype and unfavourable metabolic profiles than the MHNO group. Among MHO subjects, those who transitioned to MAO were at a 4.1-fold increased risk of incident CKD than those who regressed to MHNO. In addition, transition to MHO from other groups carried a higher risk of CKD than persistent MHNO. CONCLUSION MHO subjects are at increased risk for incident CKD.
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Affiliation(s)
- Ki Heon Nam
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea
| | - Hae-Ryong Yun
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea
| | - Young Su Joo
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea
| | - Joohwan Kim
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea
| | - Sangmi Lee
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea
| | - Changhyun Lee
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea
| | - Kyoung Sook Park
- Department of Internal Medicine, National Health Insurance Service Medical Center, Ilsan Hospital, Goyang-si, Korea
| | - Jung Tak Park
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea
| | - Tae-Ik Chang
- Department of Internal Medicine, National Health Insurance Service Medical Center, Ilsan Hospital, Goyang-si, Korea
| | - Ea Wha Kang
- Department of Internal Medicine, National Health Insurance Service Medical Center, Ilsan Hospital, Goyang-si, Korea
| | - Tae-Hyun Yoo
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea
| | - Shin-Wook Kang
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea
- Department of Internal Medicine, College of Medicine, Severance Biomedical Science Institute, Seoul, Korea
| | - Seung Hyeok Han
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea
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22
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Gerlini R, Berti L, Darr J, Lassi M, Brandmaier S, Fritsche L, Scheid F, Böhm A, Königsrainer A, Grallert H, Häring HU, Hrabě de Angelis M, Staiger H, Teperino R. Glucose tolerance and insulin sensitivity define adipocyte transcriptional programs in human obesity. Mol Metab 2018; 18:42-50. [PMID: 30309776 PMCID: PMC6308911 DOI: 10.1016/j.molmet.2018.09.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/10/2018] [Accepted: 09/12/2018] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Although debated, metabolic health characterizes 10-25% of obese individuals and reduces risk of developing life-threatening co-morbidities. Adipose tissue is a recognized endocrine organ important for the maintenance of whole-body metabolic health. Adipocyte transcriptional signatures of healthy and unhealthy obesity are largely unknown. METHODS Here, we used a small cohort of highly characterized obese individuals discordant for metabolic health, characterized their adipocytes transcriptional signatures, and cross-referenced them to mouse phenotypic and human GWAs databases. RESULTS AND CONCLUSIONS Our study showed that glucose intolerance and insulin resistance co-operate to remodel adipocyte transcriptome. We also identified the Nuclear Export Mediator Factor (NEMF) and the Ectoderm-Neural Cortex 1 (ENC1) as novel potential targets in the management of metabolic health in human obesity.
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Affiliation(s)
- R Gerlini
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research center for Environmental Health - Neuherberg, Germany; German Center for Diabetes Research (DZD) - Neuherberg, Germany
| | - L Berti
- German Center for Diabetes Research (DZD) - Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tübingen, Tübingen, Germany
| | - J Darr
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research center for Environmental Health - Neuherberg, Germany; German Center for Diabetes Research (DZD) - Neuherberg, Germany
| | - M Lassi
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research center for Environmental Health - Neuherberg, Germany; German Center for Diabetes Research (DZD) - Neuherberg, Germany
| | - S Brandmaier
- German Center for Diabetes Research (DZD) - Neuherberg, Germany; Research Unit Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology 2, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - L Fritsche
- German Center for Diabetes Research (DZD) - Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tübingen, Tübingen, Germany
| | - F Scheid
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research center for Environmental Health - Neuherberg, Germany; German Center for Diabetes Research (DZD) - Neuherberg, Germany
| | - A Böhm
- German Center for Diabetes Research (DZD) - Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tübingen, Tübingen, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
| | - A Königsrainer
- Department of General, Visceral and Transplant Surgery, University of Tübingen, Tübingen, Germany
| | - H Grallert
- German Center for Diabetes Research (DZD) - Neuherberg, Germany; Research Unit Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology 2, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - H U Häring
- German Center for Diabetes Research (DZD) - Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tübingen, Tübingen, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
| | - M Hrabě de Angelis
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research center for Environmental Health - Neuherberg, Germany; German Center for Diabetes Research (DZD) - Neuherberg, Germany; Experimental Genetics, Faculty of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
| | - H Staiger
- German Center for Diabetes Research (DZD) - Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-Karls-University of Tübingen, Tübingen, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany.
| | - R Teperino
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research center for Environmental Health - Neuherberg, Germany; German Center for Diabetes Research (DZD) - Neuherberg, Germany.
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23
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Kučera J, Spáčil Z, Friedecký D, Novák J, Pekař M, Bienertová-Vašků J. Human White Adipose Tissue Metabolome: Current Perspective. Obesity (Silver Spring) 2018; 26:1870-1878. [PMID: 30369078 DOI: 10.1002/oby.22336] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 09/09/2018] [Accepted: 09/11/2018] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Interest in metabolites produced by adipose tissue has increased substantially in the past several decades. Previously regarded as an inert energy storage depot, adipose tissue is now viewed as a complex metabolically active organ with considerable impact on human health. The emerging field of mass spectrometry-based metabolomics presents a powerful tool for the study of processes in complex biological matrices including adipose tissue. RESULTS A large number of structurally distinct metabolites can be analyzed to facilitate the investigation of differences between physiological and pathophysiological metabolic profiles associated with adipose tissue. Understanding the molecular basis of adipose tissue regulation can thereby provide insight into the monitoring of obesity-related metabolic disorders and lead to the development of novel diagnostic and prognostic biomarkers. CONCLUSIONS This review provides the current state of knowledge, recent progress, and critical evaluation of metabolomics approaches in the context of white adipose tissue and obesity. An overview of basic principles and resources describing individual groups of metabolites analyzed in white adipose tissue and biological fluids is given. The focus is on metabolites that can serve as reliable biomarkers indicative of metabolic alterations associated with obesity.
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Affiliation(s)
- Jan Kučera
- Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Zdeněk Spáčil
- Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic
| | - David Friedecký
- Laboratory of Metabolomics, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
| | - Jan Novák
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Matěj Pekař
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Surgery, Vitkovice Hospital, Ostrava, Czech Republic
| | - Julie Bienertová-Vašků
- Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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Curtasu MV, Knudsen KEB, Callesen H, Purup S, Stagsted J, Hedemann MS. Obesity Development in a Miniature Yucatan Pig Model: A Multi-compartmental Metabolomics Study on Cloned and Normal Pigs Fed Restricted or Ad Libitum High-Energy Diets. J Proteome Res 2018; 18:30-47. [PMID: 30365323 DOI: 10.1021/acs.jproteome.8b00264] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Miniature-pig models for human metabolic disorders such as obesity and metabolic syndrome are gaining popularity. However, in-depth knowledge on the phenotypic and metabolic effects of metabolic dysregulation is lacking, and ad libitum feeding is not well-characterized in these pig breeds. Therefore, an investigation was performed into the metabolome of Yucatan minipigs fed ad libitum or restricted diets. Furthermore, we used cloned and conventional minipigs to assess if cloning reflects a presumably lowered variation between subjects. For 5 months, 17 female Yucatan minipigs were fed either ad libitum or restricted Western-style diets. Serum, urine, and liver tissues were collected and analyzed by non-targeted liquid chromatography-mass spectrometry metabolomics and by biochemical analyses. Several metabolic pathways were deregulated as a result of obesity and increased energy-dense feed intake, particularly the hepatic glutathione pathway and the pantothenic acid and tryptophan metabolic pathways in serum and urine. Although cloned minipigs were phenotypically similar to wild-type minipigs, the metabolomics analysis of serum and liver tissues showed several altered pathways, such as amino acid and purine metabolism. These changes, as an effect of cloning, could limit the use of cloned models in dietary intervention studies and provides no evidence of decreased variability between subjects.
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Affiliation(s)
- Mihai V Curtasu
- Department of Animal Science , Aarhus University , Blichers Alle 20 , DK-8830 Tjele , Denmark
| | - Knud Erik B Knudsen
- Department of Animal Science , Aarhus University , Blichers Alle 20 , DK-8830 Tjele , Denmark
| | - Henrik Callesen
- Department of Animal Science , Aarhus University , Blichers Alle 20 , DK-8830 Tjele , Denmark
| | - Stig Purup
- Department of Animal Science , Aarhus University , Blichers Alle 20 , DK-8830 Tjele , Denmark
| | - Jan Stagsted
- Diet4Life , Agro Food Park 13 , DK-8200 Aarhus N , Denmark
| | - Mette S Hedemann
- Department of Animal Science , Aarhus University , Blichers Alle 20 , DK-8830 Tjele , Denmark
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Feldman A, Eder SK, Felder TK, Paulweber B, Zandanell S, Stechemesser L, Schranz M, Strebinger G, Huber-Schönauer U, Niederseer D, Patsch W, Weghuber D, Tevini J, Datz C, Aigner E. Clinical and metabolic characterization of obese subjects without non-alcoholic fatty liver: A targeted metabolomics approach. DIABETES & METABOLISM 2018; 45:132-139. [PMID: 30266576 DOI: 10.1016/j.diabet.2018.09.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 09/04/2018] [Accepted: 09/10/2018] [Indexed: 01/14/2023]
Abstract
INTRODUCTION As a small proportion of obese individuals do not develop metabolic complications and non-alcoholic fatty liver disease (NAFLD), this study aimed to provide a comprehensive clinical, metabolic and genetic description of obese subjects with healthy livers. METHODS A total of 183 subjects were stratified, according to BMI, presence of metabolic syndrome, biochemical liver tests and hepatic steatosis on ultrasound, into: (i) lean controls (n = 69); (ii) obese healthy (n = 50); and (iii)obese NAFLD (n = 62) groups. Detailed clinical, genetic and metabolic evaluations were then performed. RESULTS Obese healthy subjects did not differ in glucose parameters from lean controls, and had a lower rate of minor TM6SF2 gene variants compared with obese NAFLD (2/49 vs. 11/60, respectively; P = 0.035) and lean controls (13/64; P = 0.035), but significantly higher leptin concentrations than lean controls (P < 0.001); they also higher adiponectin concentrations (P < 0.001), and lower TNF-α and IL-6 concentrations (P = 0.01 and P < 0.001, respectively), than obese NAFLD subjects. Also, metabolomic studies identified ether- and ester-containing phospholipids [PC ae C44:6, PC ae C42:5, PC aa C40:4; P < 0.001, corrected by the false discovery rate (FDR) method] and found that the amino-acids lysine, glycine and isoleucine (FDR < 0.001) differed between the two obese groups, but not between lean controls and obese healthy subjects. CONCLUSION Obese people with healthy livers are characterized by intact glucose homoeostasis, lower pro-inflammatory cytokine levels, and higher adiponectin and leptin concentrations compared with obese people with NAFLD. In addition, the major allele of TM6SF2, a set of phosphatidylcholines and several amino acids are associated with healthy livers in obesity.
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Affiliation(s)
- A Feldman
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - S K Eder
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - T K Felder
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Department of Laboratory Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - B Paulweber
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - S Zandanell
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - L Stechemesser
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - M Schranz
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - G Strebinger
- Department of Internal Medicine, Hospital Oberndorf, Oberndorf, Austria
| | - U Huber-Schönauer
- Department of Internal Medicine, Hospital Oberndorf, Oberndorf, Austria
| | - D Niederseer
- Department of Internal Medicine, Hospital Oberndorf, Oberndorf, Austria; Department of Cardiology, University Hospital Zurich, Zurich, Switzerland
| | - W Patsch
- Department of Pharmacology and Toxicology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - D Weghuber
- Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - J Tevini
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Department of Laboratory Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - C Datz
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Department of Internal Medicine, Hospital Oberndorf, Oberndorf, Austria
| | - E Aigner
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
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Eastabrook G, Aksoy T, Bedell S, Penava D, de Vrijer B. Preeclampsia biomarkers: An assessment of maternal cardiometabolic health. Pregnancy Hypertens 2018; 13:204-213. [PMID: 30177053 DOI: 10.1016/j.preghy.2018.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 05/09/2018] [Accepted: 06/09/2018] [Indexed: 12/15/2022]
Abstract
Preeclampsia is a serious pregnancy condition defined as new-onset hypertension and proteinuria, commonly characterized as either early, 'placental', or late onset, 'maternal', using a cut-off of 34 weeks gestation. However, it may be more useful to differentiate between the vascular remodelling and placental invasion vs. inflammation and metabolic pathophysiology that underlie these forms of preeclampsia. Due to rising rates of obesity, the late-onset, maternal form is increasingly occurring earlier in pregnancy. Predictive tests for preeclampsia typically include biophysical markers such as maternal body mass index and mean arterial pressure, indicating the importance of cardiovascular and metabolic health in its pathophysiology. In contrast, the placental, inflammatory, endothelial and/or metabolic biomarkers used in these tests are generally thought to indicate an abnormal response to placentation and predict the disease. However, many of these non-placental biomarkers are known to predict impaired metabolic health in non-pregnant subjects with obesity (metabolically unhealthy obesity) and coronary artery disease or stroke in people at risk for cardiovascular events. Similarities between the performance of these markers in the prediction of cardiovascular and metabolic health outside of pregnancy suggests that they may be more indicative of maternal health than predictive for preeclampsia. This paper reviews the biophysical and biochemical markers in preeclampsia prediction and compares their performance to tests assessing metabolic health and risk of cardiovascular disease, particularly in the obese population.
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Affiliation(s)
- Genevieve Eastabrook
- Department of Obstetrics and Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute and Lawson Health Research Institute, London, Ontario, Canada.
| | - Tuba Aksoy
- Department of Obstetrics and Gynecology, Mackenzie Richmond Hill Hospital, Richmond Hill, Ontario, Canada.
| | - Samantha Bedell
- Department of Obstetrics and Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
| | - Debbie Penava
- Department of Obstetrics and Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute and Lawson Health Research Institute, London, Ontario, Canada.
| | - Barbra de Vrijer
- Department of Obstetrics and Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Children's Health Research Institute and Lawson Health Research Institute, London, Ontario, Canada.
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Individual fatty acids in erythrocyte membranes are associated with several features of the metabolic syndrome in obese children. Eur J Nutr 2018; 58:731-742. [PMID: 29594475 DOI: 10.1007/s00394-018-1677-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 03/25/2018] [Indexed: 12/15/2022]
Abstract
PURPOSE Obesity leads to the clustering of cardiovascular (CV) risk factors and the metabolic syndrome (MetS) also in children and is often accompanied by non-alcoholic fatty liver disease. Quality of dietary fat, beyond the quantity, can influence CV risk profile and, in particular, omega-3 fatty acids (FA) have been proposed as beneficial in this setting. The aim of the study was to evaluate the associations of individual CV risk factors, characterizing the MetS, with erythrocyte membrane FA, markers of average intake, in a group of 70 overweight/obese children. METHODS We conducted an observational study. Erythrocyte membrane FA were measured by gas chromatography. Spearman correlation coefficients (rS) were calculated to evaluate associations between FA and features of the MetS. RESULTS Mean content of Omega-3 FA was low (Omega-3 Index = 4.7 ± 0.8%). Not omega-3 FA but some omega-6 FA, especially arachidonic acid (AA), were inversely associated with several features of the MetS: AA resulted inversely correlated with waist circumference (rS = - 0.352), triglycerides (rS = - 0.379), fasting insulin (rS = - 0.337) and 24-h SBP (rS = - 0.313). Total amount of saturated FA (SFA) and specifically palmitic acid, correlated positively with waist circumference (rS = 0.354), triglycerides (rS = 0.400) and fasting insulin (rS = 0.287). Fatty Liver Index (FLI), a predictive score of steatosis based on GGT, triglycerides and anthropometric indexes, was positively correlated to palmitic acid (rS = 0.515) and inversely to AA (rS = - 0.472). CONCLUSIONS Our data suggest that omega-6 FA, and especially AA, could be protective toward CV risk factors featuring the MetS and also to indexes of hepatic steatosis in obese children, whereas SFA seems to exert opposite effects.
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Alizadeh S, Mirzaei K, Mohammadi C, Keshavarz SA, Maghbooli Z. Circulating omentin-1 might be associated with metabolic health status in different phenotypes of body size. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2017; 61:567-574. [PMID: 28658347 PMCID: PMC10522062 DOI: 10.1590/2359-3997000000269] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 01/23/2017] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Adipokines are mediators of body composition and are involved in obesity complications. This study aimed to assess the association of circulating omentin-1, vaspin, and RBP-4 with body composition indices and metabolic health status (MHS) in different phenotypes of body size. SUBJECTS AND METHODS A total of 350 subjects were included in the current cross-sectional study. Body composition was measured using a body composition analyzer, and serum concentrations of omentin-1, vaspin, and RBP-4 were assessed by ELISA kits. RESULTS Circulating omentin-1 was significantly (OR = 1.81, 95% CI: 1.00-1.91, P = 0.01) and marginally (OR = 1.63, 95%CI: 1.00-1.75, P = 0.06) associated with MHS in the overweight and obese subjects, respectively. But no association was seen between omentin-1 and MHS in normal-weight subjects. Serum levels of vaspin and RBP-4 were not correlated with MHS. Furthermore, a significant positive correlation was observed between circulating omentin-1 and body mass index (BMI) as well as fat percentage (P = 0.02) in the MHS group. Serum vaspin concentrations were not related to body composition components in both groups. In addition, in the MHS group, circulating RBP-4 was positively correlated with fat percentage and fat mass (FM) (p < 0.0001) and was negatively correlated with fat-free mass (FFM) and total body water (TBW) (p < 0.0001). In contrast, in the metabolically unhealthy group, RBP-4 was negatively correlated with fat percentage, FM, and BMI (p < 0.0001) and was positively correlated with FFM and TBW (p < 0.0001). CONCLUSIONS This study showed that circulating levels of omentin-1 are useful predictors of metabolic health status in overweight and obese people.
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Affiliation(s)
- Shahab Alizadeh
- Osteoporosis Research CenterEndocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIranOsteoporosis Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences (TUMS), Tehran, Iran
- Department of Cellular and Molecular NutritionSchool of Nutritional Sciences and DieteticsTUMSTehranIranDepartment of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, TUMS, Tehran, Iran
| | - Khadijeh Mirzaei
- Department of Community NutritionSchool of Nutritional Sciences and DieteticsTUMSTehranIranDepartment of Community Nutrition, School of Nutritional Sciences and Dietetics, TUMS, Tehran, Iran
| | - Chonur Mohammadi
- Osteoporosis Research CenterEndocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIranOsteoporosis Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences (TUMS), Tehran, Iran
- Department of Community NutritionSchool of Nutritional Sciences and DieteticsTUMSTehranIranDepartment of Community Nutrition, School of Nutritional Sciences and Dietetics, TUMS, Tehran, Iran
| | - Seyed Ali Keshavarz
- Department of Clinical NutritionSchool of Nutritional Sciences and DieteticsTUMSTehranIranDepartment of Clinical Nutrition, School of Nutritional Sciences and Dietetics, TUMS, Tehran, Iran
| | - Zhila Maghbooli
- Osteoporosis Research CenterEndocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIranOsteoporosis Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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Staiger H, Keuper M, Berti L, Hrabe de Angelis M, Häring HU. Fibroblast Growth Factor 21-Metabolic Role in Mice and Men. Endocr Rev 2017; 38:468-488. [PMID: 28938407 DOI: 10.1210/er.2017-00016] [Citation(s) in RCA: 197] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 07/25/2017] [Indexed: 12/18/2022]
Abstract
Since its identification in 2000, the interest of scientists in the hepatokine fibroblast growth factor (FGF) 21 has tremendously grown, and still remains high, due to a wealth of very robust data documenting this factor's favorable effects on glucose and lipid metabolism in mice. For more than ten years now, intense in vivo and ex vivo experimentation addressed the physiological functions of FGF21 in humans as well as its pathophysiological role and pharmacological effects in human metabolic disease. This work produced a comprehensive collection of data revealing overlaps in FGF21 expression and function but also significant differences between mice and humans that have to be considered before translation from bench to bedside can be successful. This review summarizes what is known about FGF21 in mice and humans with a special focus on this factor's role in glucose and lipid metabolism and in metabolic diseases, such as obesity and type 2 diabetes mellitus. We highlight the discrepancies between mice and humans and try to decipher their underlying reasons.
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Affiliation(s)
- Harald Staiger
- Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.,Interfaculty Center for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, 72076 Tübingen, Germany.,Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.,German Center for Diabetes Research, 85764 Neuherberg, Germany
| | - Michaela Keuper
- Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.,German Center for Diabetes Research, 85764 Neuherberg, Germany
| | - Lucia Berti
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, 72076 Tübingen, Germany.,Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.,German Center for Diabetes Research, 85764 Neuherberg, Germany
| | - Martin Hrabe de Angelis
- Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.,German Center for Diabetes Research, 85764 Neuherberg, Germany.,Chair for Experimental Genetics, Technical University Munich, 85764 Neuherberg, Germany
| | - Hans-Ulrich Häring
- Interfaculty Center for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, 72076 Tübingen, Germany.,German Center for Diabetes Research, 85764 Neuherberg, Germany.,Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, 72076 Tübingen, Germany
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Alfadda AA, Masood A, Al-Naami MY, Chaurand P, Benabdelkamel H. A Proteomics Based Approach Reveals Differential Regulation of Visceral Adipose Tissue Proteins between Metabolically Healthy and Unhealthy Obese Patients. Mol Cells 2017; 40:685-695. [PMID: 28927258 PMCID: PMC5638776 DOI: 10.14348/molcells.2017.0073] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Revised: 08/01/2017] [Accepted: 08/04/2017] [Indexed: 12/16/2022] Open
Abstract
Obesity and the metabolic disorders that constitute metabolic syndrome are a primary cause of morbidity and mortality in the world. Nonetheless, the changes in the proteins and the underlying molecular pathways involved in the relevant pathogenesis are poorly understood. In this study a proteomic analysis of the visceral adipose tissue isolated from metabolically healthy and unhealthy obese patients was used to identify presence of altered pathway(s) leading to metabolic dysfunction. Samples were obtained from 18 obese patients undergoing bariatric surgery and were subdivided into two groups based on the presence or absence of comorbidities as defined by the International Diabetes Federation. Two dimensional difference in-gel electrophoresis coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was carried out. A total of 28 proteins were identified with a statistically significant difference in abundance and a 1.5-fold change (ANOVA, p ≤ 0.05) between the groups. 11 proteins showed increased abundance while 17 proteins were decreased in the metabolically unhealthy obese compared to the healthy obese. The differentially expressed proteins belonged broadly to three functional categories: (i) protein and lipid metabolism (ii) cytoskeleton and (iii) regulation of other metabolic processes. Network analysis by Ingenuity pathway analysis identified the NFκB, IRK/MAPK and PKC as the nodes with the highest connections within the connectivity map. The top network pathway identified in our protein data set related to cellular movement, hematological system development and function, and immune cell trafficking. The VAT proteome between the two groups differed substantially between the groups which could potentially be the reason for metabolic dysfunction.
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Affiliation(s)
- Assim A. Alfadda
- Obesity Research Center, College of Medicine, King Saud University,
Saudi Arabia
- Department of Medicine, College of Medicine, King Saud University,
Saudi Arabia
| | - Afshan Masood
- Obesity Research Center, College of Medicine, King Saud University,
Saudi Arabia
| | | | - Pierre Chaurand
- Department of Chemistry, Université de Montréal, Montreal,
Canada
| | - Hicham Benabdelkamel
- Obesity Research Center, College of Medicine, King Saud University,
Saudi Arabia
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Chabot K, Gauthier MS, Garneau P, Rabasa-Lhoret R. Evolution of subcutaneous adipose tissue fibrosis after bariatric surgery. DIABETES & METABOLISM 2017; 43:125-133. [DOI: 10.1016/j.diabet.2016.10.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 09/15/2016] [Accepted: 10/16/2016] [Indexed: 10/20/2022]
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Baek SH, Kim M, Kim M, Kang M, Yoo HJ, Lee NH, Kim YH, Song M, Lee JH. Metabolites distinguishing visceral fat obesity and atherogenic traits in individuals with overweight. Obesity (Silver Spring) 2017; 25:323-331. [PMID: 28000430 DOI: 10.1002/oby.21724] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 10/13/2016] [Accepted: 10/17/2016] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To screen the metabolomes of both overweight subjects with low visceral fat area (LFO) and high visceral fat area (HFO) to identify potential metabolites that are associated with the different metabolic characteristics. METHODS The metabolic characteristics of 112 overweight (25 kg/m2 ≤ BMI < 30 kg/m2 ) Korean individuals aged 30 to 65 years were examined. Plasma metabolomic profiling of HFO [visceral fat area (VFA) at L4 ≥ 100 cm2 ] and LFO (L4 VFA <100 cm2 ) individuals matched for age, gender, and BMI was performed. RESULTS HFO subjects showed higher VFA at L1 and L4 than LFO subjects. The HFO group showed higher blood pressure, lipid profile, high-sensitivity C-reactive protein, malondialdehyde, oxidized low-density lipoprotein (LDL), and homeostasis model assessment-insulin resistance and lower high-density lipoprotein-cholesterol levels. In plasma metabolite identification, the HFO group showed significantly higher levels of long-chain (C14:1, C16:1, C16) acylcarnitines (ACs), medium-chain (C12:1, C12) ACs, urobilinogen, docosahexaenoic acid (C22:6ω3), lysoPE (22:6), lysoPC (22:6), lysoPC (22:5), methoxybenzenepropanoic acid, and isodesmosine. All five ACs correlated positively with VFA and oxidized LDL levels and negatively with high-density lipoprotein-cholesterol levels and LDL particle size. CONCLUSIONS Twelve major metabolites, including three long-chain fatty acids and two medium-chain ACs, are important for distinguishing HFO and LFO. Chronic lipid surplus from visceral fat in HFO is likely associated with substantial increases in plasma medium-chain ACs and long-chain fatty acids, which are closely related to atherogenic traits.
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Affiliation(s)
- Seung Han Baek
- Institute of Convergence Technology, Yonsei University, Seoul, Korea
| | - Minkyung Kim
- Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, Korea
| | - Minjoo Kim
- Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, Korea
| | - Miso Kang
- Department of Food and Nutrition, National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, College of Human Ecology, Yonsei University, Seoul, Korea
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Hye Jin Yoo
- Department of Food and Nutrition, National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, College of Human Ecology, Yonsei University, Seoul, Korea
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Nan Hee Lee
- Department of Food and Nutrition, National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, College of Human Ecology, Yonsei University, Seoul, Korea
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Yong Hwan Kim
- Department of Library and Information Science, Yonsei University, Seoul, Korea
| | - Min Song
- Department of Library and Information Science, Yonsei University, Seoul, Korea
| | - Jong Ho Lee
- Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, Korea
- Department of Food and Nutrition, National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, College of Human Ecology, Yonsei University, Seoul, Korea
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
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Abstract
PURPOSE OF REVIEW Purpose of review: It is becoming increasingly clear that some obese individuals do not develop dyslipidemia and instead remain healthy, while some normal weight individuals become dyslipidemic and unhealthy. RECENT FINDINGS The present review examines the similarities and differences between healthy and unhealthy individuals with and without obesity and discusses putative underlying mechanisms of dyslipidemia. The presence of dyslipidemia and compromised metabolic health in both lean and obese individuals suggests that the obese phenotype per se does not represent a main independent risk factor for the development of dyslipidemia and that dyslipidemia, rather than obesity, may be the driver of metabolic diseases. Notably, adipose tissue dysfunction and ectopic lipid deposition, in particular in the liver, seems a common trait of unhealthy individuals.
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Affiliation(s)
- David H Ipsen
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark
| | - Pernille Tveden-Nyborg
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark
| | - Jens Lykkesfeldt
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark.
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Berti L, Hartwig S, Irmler M, Rädle B, Siegel-Axel D, Beckers J, Lehr S, Al-Hasani H, Häring HU, Hrabě de Angelis M, Staiger H. Impact of fibroblast growth factor 21 on the secretome of human perivascular preadipocytes and adipocytes: a targeted proteomics approach. Arch Physiol Biochem 2016; 122:281-288. [PMID: 27494767 DOI: 10.1080/13813455.2016.1212898] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
CONTEXT Perivascular adipose tissue (PVAT) is suggested to impact on vascular cells via humoral factors, possibly contributing to endothelial dysfunction and atherosclerosis. OBJECTIVE To address whether the hepatokine fibroblast growth factor (FGF) 21 affects the PVAT secretome. METHODS Human perivascular (pre)adipocytes were subjected to targeted proteomics and whole-genome gene expression analysis. RESULTS Preadipocytes, as compared to adipocytes, secreted higher amounts of inflammatory cytokines and chemokines. Adipocytes released higher amounts of adipokines [e.g. adipisin, visfatin, dipeptidyl peptidase 4 (DPP4), leptin; p < 0.05, all]. In preadipocytes, omentin 1 release was 1.28-fold increased by FGF-21 (p < 0.05). In adipocytes, FGF-21 reduced chemerin release by 5% and enhanced DPP4 release by 1.15-fold (p < 0.05, both). FGF-21 altered the expression of four secretory genes in preadipocytes and of 18 in adipocytes (p < 0.01, all). CONCLUSION The hepatokine FGF-21 exerts secretome-modulating effects in human perivascular (pre)adipocytes establishing a new liver-PVAT-blood vessel axis that possibly contributes to vascular inflammation and atherosclerosis.
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Affiliation(s)
- Lucia Berti
- a Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen , Tübingen , Germany
- b Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Experimental Genetics , Neuherberg , Germany
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
| | - Sonja Hartwig
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
- d Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich Heine University Düsseldorf , Düsseldorf , Germany
| | - Martin Irmler
- b Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Experimental Genetics , Neuherberg , Germany
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
| | - Bernhard Rädle
- b Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Experimental Genetics , Neuherberg , Germany
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
| | - Dorothea Siegel-Axel
- a Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen , Tübingen , Germany
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
- e Department of Internal Medicine , Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen , Tübingen , Germany , and
| | - Johannes Beckers
- b Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Experimental Genetics , Neuherberg , Germany
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
- f Chair for Experimental Genetics, Technical University Munich , Neuherberg , Germany
| | - Stefan Lehr
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
- d Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich Heine University Düsseldorf , Düsseldorf , Germany
| | - Hadi Al-Hasani
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
- d Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich Heine University Düsseldorf , Düsseldorf , Germany
| | - Hans-Ulrich Häring
- a Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen , Tübingen , Germany
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
- e Department of Internal Medicine , Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen , Tübingen , Germany , and
| | - Martin Hrabě de Angelis
- b Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Experimental Genetics , Neuherberg , Germany
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
- f Chair for Experimental Genetics, Technical University Munich , Neuherberg , Germany
| | - Harald Staiger
- a Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen , Tübingen , Germany
- c German Centre for Diabetes Research (DZD) , Neuherberg , Germany
- e Department of Internal Medicine , Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen , Tübingen , Germany , and
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Zhou Y, Orešič M, Leivonen M, Gopalacharyulu P, Hyysalo J, Arola J, Verrijken A, Francque S, Van Gaal L, Hyötyläinen T, Yki-Järvinen H. Noninvasive Detection of Nonalcoholic Steatohepatitis Using Clinical Markers and Circulating Levels of Lipids and Metabolites. Clin Gastroenterol Hepatol 2016; 14:1463-1472.e6. [PMID: 27317851 DOI: 10.1016/j.cgh.2016.05.046] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 05/05/2016] [Accepted: 05/16/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Use of targeted mass spectrometry (MS)-based methods is increasing in clinical chemistry laboratories. We investigate whether MS-based profiling of plasma improves noninvasive risk estimates of nonalcoholic steatohepatitis (NASH) compared with routinely available clinical parameters and patatin-like phospholipase domain-containing protein 3 (PNPLA3) genotype at rs738409. METHODS We used MS-based analytic platforms to measure levels of lipids and metabolites in blood samples from 318 subjects who underwent a liver biopsy because of suspected NASH. The subjects were divided randomly into estimation (n = 223) and validation (n = 95) groups to build and validate the model. Gibbs sampling and stepwise logistic regression, which fulfilled the Bayesian information criterion, were used for variable selection and modeling. RESULTS Features of the metabolic syndrome and the variant in PNPLA3 encoding I148M were significantly more common among subjects with than without NASH. We developed a model to identify subjects with NASH based on clinical data and PNPLA3 genotype (NASH Clin Score), which included aspartate aminotransferase (AST), fasting insulin, and PNPLA3 genotype. This model identified subjects with NASH with an area under the receiver operating characteristic of 0.778 (95% confidence interval, 0.709-0.846). We then used backward stepwise logistic regression analyses of variables from the NASH Clin Score and MS-based factors associated with NASH to develop the NASH ClinLipMet Score. This included glutamate, isoleucine, glycine, lysophosphatidylcholine 16:0, phosphoethanolamine 40:6, AST, and fasting insulin, along with PNPLA3 genotype. It identified patients with NASH with an area under the receiver operating characteristic of 0.866 (95% confidence interval, 0.820-0.913). The NASH ClinLipMet score identified patients with NASH with significantly higher accuracy than the NASH Clin Score or MS-based profiling alone. CONCLUSIONS A score based on MS (glutamate, isoleucine, glycine, lysophosphatidylcholine 16:0, phosphoethanolamine 40:6) and knowledge of AST, fasting insulin, and PNPLA3 genotype is significantly better than a score based on clinical or metabolic profiles alone in determining the risk of NASH.
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Affiliation(s)
- You Zhou
- Minerva Foundation Institute for Medical Research, Helsinki, Finland; Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | | | - Marja Leivonen
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | | | - Jenni Hyysalo
- Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - An Verrijken
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Luc Van Gaal
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | | | - Hannele Yki-Järvinen
- Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki, Helsinki, Finland.
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Gao X, Zhang W, Wang Y, Pedram P, Cahill F, Zhai G, Randell E, Gulliver W, Sun G. Serum metabolic biomarkers distinguish metabolically healthy peripherally obese from unhealthy centrally obese individuals. Nutr Metab (Lond) 2016; 13:33. [PMID: 27175209 PMCID: PMC4865032 DOI: 10.1186/s12986-016-0095-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/03/2016] [Indexed: 12/11/2022] Open
Abstract
Background Metabolic abnormalities are more associated with central obesity than peripheral obesity, but the underlying mechanisms are largely unknown. The present study was to identify serum metabolic biomarkers which distinguish metabolically unhealthy centrally obese (MUCO) from metabolically healthy peripherally obese (MHPO) individuals. Methods A two-stage case–control study design was employed. In the discovery stage, 20 individuals (10 MHPO and 10 MUCO) were included and in the following validation stage, 79 individuals (20 normal weight (NW), 30 MHPO, 29 MUCO) were utilized. Study groups were matched for age, sex, physical activity and total dietary calorie intake with MHPO and MUCO additionally matched for BMI. Metabolic abnormality was defined as: 1) HOMA-IR > 4.27 (90th percentile), 2) high-density lipoprotein cholesterol < 1.03 mmol/L in men and < 1.30 mmol/L in women, 3) fasting blood glucose ≥ 5.6 mmol/L, and 4) waist circumference > 102 cm in men and > 88 cm in women. MUCO individuals had all of these abnormalities whereas MHPO and NW individuals had none of them. A targeted metabolomics approach was performed on fasting serum samples, which can simultaneously identify and quantify 186 metabolites. Results In the discovery stage, serum leucine, isoleucine, tyrosine, valine, phenylalanine, alpha-aminoadipic acid, methioninesulfoxide and propionylcarnitine were found to be significantly higher in MUCO, compared with MHPO group after multiple testing adjustment. Significant changes of five metabolites (leucine, isoleucine, valine, alpha-aminoadipic acid, propionylcarnitine) were confirmed in the validation stage. Conclusions Significantly higher levels of serum leucine, isoleucine, valine, alpha-aminoadipic acid, propionylcarnitine are characteristic of metabolically unhealthy centrally obese patients. The finding provides novel insights into the pathogenesis of metabolic abnormalities in obesity. Electronic supplementary material The online version of this article (doi:10.1186/s12986-016-0095-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiang Gao
- College of Food Science and Engineering, Ocean University of China, No.5, Yu Shan Road, Qingdao, Shandong Province China ; Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, NL Canada
| | - Weidong Zhang
- Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, NL Canada
| | - Yongbo Wang
- Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, NL Canada ; Department of Endocrinology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116000 Liaoning China
| | - Pardis Pedram
- Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, NL Canada
| | - Farrell Cahill
- Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, NL Canada
| | - Guangju Zhai
- Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, NL Canada
| | - Edward Randell
- Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, NL Canada
| | - Wayne Gulliver
- Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, NL Canada
| | - Guang Sun
- Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, NL Canada
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Panneerselvam J, Xie G, Che R, Su M, Zhang J, Jia W, Fei P. Distinct Metabolic Signature of Human Bladder Cancer Cells Carrying an Impaired Fanconi Anemia Tumor-Suppressor Signaling Pathway. J Proteome Res 2016; 15:1333-41. [PMID: 26956768 DOI: 10.1021/acs.jproteome.6b00076] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Metabolic profiling has great potential to help the diagnosis and prognosis of cancer patients. Fanconi Anemia (FA) tumor-suppressor signaling has been instrumental in understanding human tumorigenesis. However, this instrumental understanding has never been demonstrated at the metabolic level. Here, we show that impaired FA signaling can lead cells to exhibit metabolic signatures of tumorigenesis. This is consistent with our original studies of the roles of FA signaling in suppressing non-FA tumorigenesis at functional and genetic levels. Using ultraperformance liquid chromatography-mass spectroscopy and gas chromatography-mass spectrometry, we characterized metabolic alterations in bladder cancer cells carrying an intact or impaired FA pathway. The latter was obtained by ectopically expressing FAVL (FAVL-high), which we previously found to be capable of inactivating FA signaling. A total of 18 metabolites, end products of cell proliferation or apoptosis, were significantly different between FAVL-high and -low cells. Methionine, phenylalanine, and threonine, resulting from a tumorigenic process, were substantially increased in FAVL-high cells. With this study, we achieved genomic, functional, and metabolomic characterization of the roles of FA signaling in the development of human cancer. Furthermore, this study provides novel insights into how to translate FA basic research into strategies for producing effective biomarkers in human cancer diagnosis and prognosis.
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Affiliation(s)
- Jayabal Panneerselvam
- University of Hawaii Cancer Center, University of Hawaii , Honolulu, Hawaii, 96813 United States
| | - Guoxiang Xie
- University of Hawaii Cancer Center, University of Hawaii , Honolulu, Hawaii, 96813 United States
| | - Raymond Che
- University of Hawaii Cancer Center, University of Hawaii , Honolulu, Hawaii, 96813 United States
| | - Mingming Su
- University of Hawaii Cancer Center, University of Hawaii , Honolulu, Hawaii, 96813 United States
| | - Jun Zhang
- Department of Laboratory Medicine and Pathology, Mayo Clinic Foundation , Rochester, Minnesota, 55905 United States
| | - Wei Jia
- University of Hawaii Cancer Center, University of Hawaii , Honolulu, Hawaii, 96813 United States
| | - Peiwen Fei
- University of Hawaii Cancer Center, University of Hawaii , Honolulu, Hawaii, 96813 United States
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Granulocyte colony-stimulating factor (G-CSF): A saturated fatty acid-induced myokine with insulin-desensitizing properties in humans. Mol Metab 2016; 5:305-316. [PMID: 27069870 PMCID: PMC4812007 DOI: 10.1016/j.molmet.2016.02.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 02/02/2016] [Accepted: 02/08/2016] [Indexed: 01/01/2023] Open
Abstract
Objective Circulating long-chain free fatty acids (FFAs) are important metabolic signals that acutely enhance fatty acid oxidation, thermogenesis, energy expenditure, and insulin secretion. However, if chronically elevated, they provoke inflammation, insulin resistance, and β-cell failure. Moreover, FFAs act via multiple signaling pathways as very potent regulators of gene expression. In human skeletal muscle cells differentiated in vitro (myotubes), we have shown in previous studies that the expression of CSF3, the gene encoding granulocyte colony-stimulating factor (G-CSF), is markedly induced upon FFA treatment and exercise. Methods and results We now report that CSF3 is induced in human myotubes by saturated, but not unsaturated, FFAs via Toll-like receptor 4-dependent and -independent pathways including activation of Rel-A, AP-1, C/EBPα, Src, and stress kinases. Furthermore, we show that human adipocytes and myotubes treated with G-CSF become insulin-resistant. In line with this, a functional polymorphism in the CSF3 gene affects adipose tissue- and whole-body insulin sensitivity and glucose tolerance in human subjects with elevated plasma FFA concentrations. Conclusion G-CSF emerges as a new player in FFA-induced insulin resistance and thus may be of interest as a target for prevention and treatment of type 2 diabetes.
CSF3, the gene encoding G-CSF, is induced in human myotubes by saturated, but not unsaturated, FFAs. CSF3 expression is induced via Toll-like receptor 4-dependent and -independent pathways. Human adipocytes and myotubes treated with G-CSF become insulin-resistant. A CSF3 SNP affects insulin sensitivity and glucose tolerance in human subjects with elevated plasma FFA concentrations. G-CSF emerges as a new player in FFA-induced insulin resistance.
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Müller G. Personalized Diagnosis and Therapy. DRUG DISCOVERY AND EVALUATION: PHARMACOLOGICAL ASSAYS 2016:3167-3284. [DOI: 10.1007/978-3-319-05392-9_152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Saponaro C, Gaggini M, Carli F, Gastaldelli A. The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis. Nutrients 2015; 7:9453-74. [PMID: 26580649 PMCID: PMC4663603 DOI: 10.3390/nu7115475] [Citation(s) in RCA: 355] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 10/19/2015] [Accepted: 10/29/2015] [Indexed: 12/17/2022] Open
Abstract
Excessive accumulation of lipids can lead to lipotoxicity, cell dysfunction and alteration in metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas and muscle. This is now a recognized risk factor for the development of metabolic disorders, such as obesity, diabetes, fatty liver disease (NAFLD), cardiovascular diseases (CVD) and hepatocellular carcinoma (HCC). The causes for lipotoxicity are not only a high fat diet but also excessive lipolysis, adipogenesis and adipose tissue insulin resistance. The aims of this review are to investigate the subtle balances that underlie lipolytic, lipogenic and oxidative pathways, to evaluate critical points and the complexities of these processes and to better understand which are the metabolic derangements resulting from their imbalance, such as type 2 diabetes and non alcoholic fatty liver disease.
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Affiliation(s)
- Chiara Saponaro
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, via Moruzzi, 1 56124 Pisa, Italy.
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, 53100 Siena, Italy.
| | - Melania Gaggini
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, via Moruzzi, 1 56124 Pisa, Italy.
- Dipartimento di Patologia Chirurgica, Molecolare Medica e di Area Critica, Università di Pisa, 56126 Pisa, Italy.
| | - Fabrizia Carli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, via Moruzzi, 1 56124 Pisa, Italy.
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, via Moruzzi, 1 56124 Pisa, Italy.
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Brunius C, Shi L, Landberg R. Metabolomics for Improved Understanding and Prediction of Cardiometabolic Diseases—Recent Findings from Human Studies. Curr Nutr Rep 2015. [DOI: 10.1007/s13668-015-0144-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Halama A, Guerrouahen BS, Pasquier J, Diboun I, Karoly ED, Suhre K, Rafii A. Metabolic signatures differentiate ovarian from colon cancer cell lines. J Transl Med 2015; 13:223. [PMID: 26169745 PMCID: PMC4499939 DOI: 10.1186/s12967-015-0576-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 06/17/2015] [Indexed: 12/22/2022] Open
Abstract
Background In this era of precision medicine, the deep and comprehensive characterization of tumor phenotypes will lead to therapeutic strategies beyond classical factors such as primary sites or anatomical staging. Recently, “-omics” approached have enlightened our knowledge of tumor biology. Such approaches have been extensively implemented in order to provide biomarkers for monitoring of the disease as well as to improve readouts of therapeutic impact. The application of metabolomics to the study of cancer is especially beneficial, since it reflects the biochemical consequences of many cancer type-specific pathophysiological processes. Here, we characterize metabolic profiles of colon and ovarian cancer cell lines to provide broader insight into differentiating metabolic processes for prospective drug development and clinical screening. Methods We applied non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography and gas chromatography for the metabolic phenotyping of four cancer cell lines: two from colon cancer (HCT15, HCT116) and two from ovarian cancer (OVCAR3, SKOV3). We used the MetaP server for statistical data analysis. Results A total of 225 metabolites were detected in all four cell lines; 67 of these molecules significantly discriminated colon cancer from ovarian cancer cells. Metabolic signatures revealed in our study suggest elevated tricarboxylic acid cycle and lipid metabolism in ovarian cancer cell lines, as well as increased β-oxidation and urea cycle metabolism in colon cancer cell lines. Conclusions Our study provides a panel of distinct metabolic fingerprints between colon and ovarian cancer cell lines. These may serve as potential drug targets, and now can be evaluated further in primary cells, biofluids, and tissue samples for biomarker purposes. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0576-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Anna Halama
- Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Qatar-Foundation, P.O. Box 24144, Doha, Qatar.
| | - Bella S Guerrouahen
- Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar. .,Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA. .,Experimental Biology Division-Research, Sidra Medical and Research Center, PO Box 26999, Doha, Qatar.
| | - Jennifer Pasquier
- Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar. .,Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
| | - Ilhem Diboun
- Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Qatar-Foundation, P.O. Box 24144, Doha, Qatar.
| | | | - Karsten Suhre
- Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Qatar-Foundation, P.O. Box 24144, Doha, Qatar. .,Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
| | - Arash Rafii
- Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar. .,Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA. .,Department of Genetic Medicine and Obstetrics and Gynecology, Weill Cornell Medical College, Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Qatar-Foundation, P.O. Box 24144, Doha, Qatar.
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Berti L, Irmler M, Zdichavsky M, Meile T, Böhm A, Stefan N, Fritsche A, Beckers J, Königsrainer A, Häring HU, de Angelis MH, Staiger H. Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes. Mol Metab 2015; 4:519-27. [PMID: 26137439 PMCID: PMC4481465 DOI: 10.1016/j.molmet.2015.04.002] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 04/20/2015] [Accepted: 04/23/2015] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE Serum concentrations of the hepatokine fibroblast growth factor (FGF) 21 are elevated in obesity, type-2 diabetes, and the metabolic syndrome. We asked whether FGF21 levels differ between subjects with metabolically healthy vs. unhealthy obesity (MHO vs. MUHO), opening the possibility that FGF21 is a cross-talker between liver and adipose tissue in MUHO. Furthermore, we studied the effects of chronic FGF21 treatment on adipocyte differentiation, lipid storage, and adipokine secretion. METHODS In 20 morbidly obese donors of abdominal subcutaneous fat biopsies discordant for their whole-body insulin sensitivity (hereby classified as MHO or MUHO subjects), serum FGF21 was quantified. The impact of chronic FGF21 treatment on differentiation, lipid accumulation, and adipokine release was assessed in isolated preadipocytes differentiated in vitro. RESULTS Serum FGF21 concentrations were more than two-fold higher in MUHO as compared to MHO subjects (457 ± 378 vs. 211 ± 123 pg/mL; p < 0.05). FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p < 0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, -15% and -40%, respectively; p < 0.01 both), reduced adiponectin expression (-20%; p < 0.05), markedly reduced adiponectin release (-60%; p < 0.01), and substantially increased leptin (+60%; p < 0.01) and interleukin-6 (+50%; p < 0.001) release. CONCLUSIONS The hepatokine FGF21 exerts weak lipogenic and anti-adipogenic actions and marked adiponectin-suppressive and leptin and interleukin-6 release-promoting effects in human differentiating preadipocytes. Together with the higher serum concentrations in MUHO subjects, our findings reveal FGF21 as a circulating factor promoting the development of metabolically unhealthy adipocytes.
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Key Words
- AMPK, AMP-activated protein kinase
- Adipokine
- Adiponectin
- BMI, body mass index
- C/EBP-α, CCAAT/enhancer-binding protein-α
- CIDEA, cell death-inducing DNA fragmentation factor-like effector a
- ERK, extracellular signal-regulated kinase
- FGF, fibroblast growth factor
- FGF21
- GAPDH, glyceraldehyde 3-phosphate dehydrogenase
- Hepatokine
- IL-6, interleukin-6
- MHO, metabolically healthy obesity
- MUHO, metabolically unhealthy obesity
- PGC-1α, PPAR-γ coactivator-1α
- PPAR-γ, peroxisome proliferator-activated receptor-γ
- Secretome
- Type-2 diabetes
- UCP-1, uncoupling protein-1
- hasc, human abdominal subcutaneous
- qPCR, quantitative polymerase chain reaction
- rh, recombinant human
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Affiliation(s)
- Lucia Berti
- Institute of Experimental Genetics, Helmholtz Centre Munich GmbH, German Research Centre for Environmental Health, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany
| | - Martin Irmler
- Institute of Experimental Genetics, Helmholtz Centre Munich GmbH, German Research Centre for Environmental Health, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany
| | - Marty Zdichavsky
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Straße 3, D-72076 Tübingen, Germany
| | - Tobias Meile
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Straße 3, D-72076 Tübingen, Germany
| | - Anja Böhm
- German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany ; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany
| | - Norbert Stefan
- German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany ; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany
| | - Andreas Fritsche
- German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany ; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany
| | - Johannes Beckers
- Institute of Experimental Genetics, Helmholtz Centre Munich GmbH, German Research Centre for Environmental Health, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Chair for Experimental Genetics, Technical University Munich, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany
| | - Alfred Königsrainer
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Straße 3, D-72076 Tübingen, Germany
| | - Hans-Ulrich Häring
- German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany ; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany
| | - Martin Hrabě de Angelis
- Institute of Experimental Genetics, Helmholtz Centre Munich GmbH, German Research Centre for Environmental Health, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Chair for Experimental Genetics, Technical University Munich, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany
| | - Harald Staiger
- German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany ; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany
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Tomei S, Mamtani R, Al Ali R, Elkum N, Abdulmalik M, Ismail A, Cheema S, Rouh HA, Aigha II, Hani F, Al-Samraye S, Taher Aseel M, El Emadi N, Al Mujalli A, Abdelkerim A, Youssif S, Worschech A, El Sebakhy E, Temanni R, Khanna V, Wang E, Kizhakayil D, Al-Thani AA, Al-Thani M, Lowenfels A, Marincola FM, Sheikh J, Chouchane L. Obesity susceptibility loci in Qataris, a highly consanguineous Arabian population. J Transl Med 2015; 13:119. [PMID: 25890290 PMCID: PMC4422146 DOI: 10.1186/s12967-015-0459-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Accepted: 03/10/2015] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVES In Qataris, a population characterized by a small size and a high rate of consanguinity, between two-thirds to three-quarters of adults are overweight or obese. We investigated the relevance of 23 obesity-related loci in the Qatari population. METHODS Eight-hundred-four individuals assessed to be third generation Qataris were included in the study and assigned to 3 groups according to their body mass index (BMI): 190 lean (BMI < 25 kg/m(2)); 131 overweight (25 kg/m(2) ≤ BMI < 30 kg/m(2)) and 483 obese (BMI ≥ 30 kg/m(2)). Genomic DNA was isolated from peripheral blood and genotyped by TaqMan. RESULTS Two loci significantly associated with obesity in Qataris: the TFAP2B variation (rs987237) (A allele versus G allele: chi-square = 10.3; P = 0.0013) and GNPDA2 variation (rs10938397) (A allele versus G allele: chi-square = 6.15; P = 0.013). The TFAP2B GG genotype negatively associated with obesity (OR = 0.21; P = 0.0031). Conversely, the GNDPA2 GG homozygous genotype associated with higher risk of obesity in subjects of age < 32 years (P = 0.0358). CONCLUSION We showed a different genetic profile associated with obesity in the Qatari population compared to Western populations. Studying the genetic background of Qataris is of primary importance as the etiology of a given disease might be population-specific.
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Affiliation(s)
- Sara Tomei
- Department of Genetic Medicine, Laboratory of Genetic Medicine & Immunology, Weill Cornell Medical College in Qatar, Al Luqta Street, Qatar Foundation, Education City, Doha, Qatar, PO 24144. .,Sidra Medical and Research Center, Research Branch, Al Nasr Tower, Al Corniche Street, Qatar Foundation, Doha, Qatar, PO 26999.
| | - Ravinder Mamtani
- Global and Public Health Department, Weill Cornell Medical College in Qatar, Doha, Qatar.
| | - Rashid Al Ali
- Sidra Medical and Research Center, Research Branch, Al Nasr Tower, Al Corniche Street, Qatar Foundation, Doha, Qatar, PO 26999.
| | - Naser Elkum
- Sidra Medical and Research Center, Research Branch, Al Nasr Tower, Al Corniche Street, Qatar Foundation, Doha, Qatar, PO 26999.
| | | | - Awatef Ismail
- Global and Public Health Department, Weill Cornell Medical College in Qatar, Doha, Qatar.
| | - Sohaila Cheema
- Global and Public Health Department, Weill Cornell Medical College in Qatar, Doha, Qatar.
| | - Hekmat A Rouh
- Global and Public Health Department, Weill Cornell Medical College in Qatar, Doha, Qatar.
| | - Idil I Aigha
- Department of Genetic Medicine, Laboratory of Genetic Medicine & Immunology, Weill Cornell Medical College in Qatar, Al Luqta Street, Qatar Foundation, Education City, Doha, Qatar, PO 24144.
| | - Fatima Hani
- Department of Genetic Medicine, Laboratory of Genetic Medicine & Immunology, Weill Cornell Medical College in Qatar, Al Luqta Street, Qatar Foundation, Education City, Doha, Qatar, PO 24144.
| | - Sura Al-Samraye
- Global and Public Health Department, Weill Cornell Medical College in Qatar, Doha, Qatar.
| | | | | | | | | | | | - Andrea Worschech
- Department of Genetic Medicine, Laboratory of Genetic Medicine & Immunology, Weill Cornell Medical College in Qatar, Al Luqta Street, Qatar Foundation, Education City, Doha, Qatar, PO 24144.
| | - Emad El Sebakhy
- Sidra Medical and Research Center, Research Branch, Al Nasr Tower, Al Corniche Street, Qatar Foundation, Doha, Qatar, PO 26999.
| | - Ramzi Temanni
- Sidra Medical and Research Center, Research Branch, Al Nasr Tower, Al Corniche Street, Qatar Foundation, Doha, Qatar, PO 26999.
| | - Vineesh Khanna
- Sidra Medical and Research Center, Research Branch, Al Nasr Tower, Al Corniche Street, Qatar Foundation, Doha, Qatar, PO 26999.
| | - Ena Wang
- Sidra Medical and Research Center, Research Branch, Al Nasr Tower, Al Corniche Street, Qatar Foundation, Doha, Qatar, PO 26999.
| | - Dhanya Kizhakayil
- Department of Genetic Medicine, Laboratory of Genetic Medicine & Immunology, Weill Cornell Medical College in Qatar, Al Luqta Street, Qatar Foundation, Education City, Doha, Qatar, PO 24144.
| | | | | | | | - Francesco M Marincola
- Sidra Medical and Research Center, Research Branch, Al Nasr Tower, Al Corniche Street, Qatar Foundation, Doha, Qatar, PO 26999.
| | - Javaid Sheikh
- Dean's Office, Weill Cornell Medical College in Qatar, Doha, Qatar.
| | - Lotfi Chouchane
- Department of Genetic Medicine, Laboratory of Genetic Medicine & Immunology, Weill Cornell Medical College in Qatar, Al Luqta Street, Qatar Foundation, Education City, Doha, Qatar, PO 24144.
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Badoud F, Perreault M, Zulyniak MA, Mutch DM. Molecular insights into the role of white adipose tissue in metabolically unhealthy normal weight and metabolically healthy obese individuals. FASEB J 2014; 29:748-58. [PMID: 25411437 DOI: 10.1096/fj.14-263913] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Obesity is a risk factor for the development of type 2 diabetes and cardiovascular disease. However, it is now recognized that a subset of individuals have reduced cardiometabolic risk despite being obese. Paradoxically, a subset of lean individuals is reported to have high risk for cardiometabolic complications. These distinct subgroups of individuals are referred to as metabolically unhealthy normal weight (MUNW) and metabolically healthy obese (MHO). Although the clinical relevance of these subgroups remains debated, evidence shows a critical role for white adipose tissue (WAT) function in the development of these phenotypes. The goal of this review is to provide an overview of our current state of knowledge regarding the molecular and metabolic characteristics of WAT associated with MUNW and MHO. In particular, we discuss the link between different WAT depots, immune cell infiltration, and adipokine production with MUNW and MHO. Furthermore, we also highlight recent molecular insights made with genomic technologies showing that processes such as oxidative phosphorylation, branched-chain amino acid catabolism, and fatty acid β-oxidation differ between these phenotypes. This review provides evidence that WAT function is closely linked with cardiometabolic risk independent of obesity and thus contributes to the development of MUNW and MHO.
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Affiliation(s)
- Flavia Badoud
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Maude Perreault
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Michael A Zulyniak
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - David M Mutch
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
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