scholarly journals Regulatory modules of human thermogenic adipocytes: functional genomics of large cohort and Meta-analysis derived marker-genes

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Beáta B. Tóth ◽  
Zoltán Barta ◽  
Ákos Barnabás Barta ◽  
László Fésüs
Keyword(s):  
Functional Genomics ◽  
Meta Analysis ◽  
Interaction Network ◽  
Regulatory Elements ◽  
Integrative Approach ◽  
Marker Genes ◽  
Biological Processes ◽  
White Adipocyte ◽  
Regulatory Modules ◽  
White Adipocytes

Abstract Background Recently, ProFAT and BATLAS studies identified brown and white adipocytes marker genes based on analysis of large databases. They offered scores to determine the thermogenic status of adipocytes using the gene-expression data of these markers. In this work, we investigated the functional context of these genes. Results Gene Set Enrichment Analyses (KEGG, Reactome) of the BATLAS and ProFAT marker-genes identified pathways deterministic in the formation of brown and white adipocytes. The collection of the annotated proteins of the defined pathways resulted in expanded white and brown characteristic protein-sets, which theoretically contain all functional proteins that could be involved in the formation of adipocytes. Based on our previously obtained RNA-seq data, we visualized the expression profile of these proteins coding genes and found patterns consistent with the two adipocyte phenotypes. The trajectory of the regulatory processes could be outlined by the transcriptional profile of progenitor and differentiated adipocytes, highlighting the importance of suppression processes in browning. Protein interaction network-based functional genomics by STRING, Cytoscape and R-Igraph platforms revealed that different biological processes shape the brown and white adipocytes and highlighted key regulatory elements and modules including GAPDH-CS, DECR1, SOD2, IL6, HRAS, MTOR, INS-AKT, ERBB2 and 4-NFKB, and SLIT-ROBO-MAPK. To assess the potential role of a particular protein in shaping adipocytes, we assigned interaction network location-based scores (betweenness centrality, number of bridges) to them and created a freely accessible platform, the AdipoNET (https//adiponet.com), to conveniently use these data. The Eukaryote Promoter Database predicted the response elements in the UCP1 promoter for the identified, potentially important transcription factors (HIF1A, MYC, REL, PPARG, TP53, AR, RUNX, and FoxO1). Conclusion Our integrative approach-based results allowed us to investigate potential regulatory elements of thermogenesis in adipose tissue. The analyses revealed that some unique biological processes form the brown and white adipocyte phenotypes, which presumes the existence of the transitional states. The data also suggests that the two phenotypes are not mutually exclusive, and differentiation of thermogenic adipocyte requires induction of browning as well as repressions of whitening. The recognition of these simultaneous actions and the identified regulatory modules can open new direction in obesity research.

scholarly journals Regulatory Modules of Human Thermogenic Adipocytes: Functional Genomics of Meta-Analyses Derived Marker-Genes

2021 ◽  
Author(s):  
Beáta B. Tóth ◽  
Zoltán Barta ◽  
László Fésüs
Keyword(s):  
Functional Genomics ◽  
Marker Gene ◽  
Marker Genes ◽  
List Type ◽  
White Adipocyte ◽  
Regulatory Modules ◽  
Network Analyses ◽  
Extended Analysis ◽  
Thermogenic Adipocytes ◽  
Meta Analyses

SummaryRecently, ProFAT and BATLAS scores have been offered to determine thermogenic status of adipocytes using expression pattern of brown and white marker-genes. In this work, we investigated the functional context of these genes. Although the two meta-analyses based marker-gene lists have little overlap, their enriched pathways show strong coincides suggesting they may better characterize adipocytes. We demonstrate that functional genomics of the annotated genes in common pathways enables an extended analysis of thermogenesis regulation, generates testable hypotheses supported by experimental results in human adipocytes with different browning potential and may lead to more global conclusions than single-state studies. Our results imply that different biological processes shape brown and white adipocytes with presumed transitional states. We propose that the thermogenic adipocyte phenotype require both repression of whitening and induction of browning. These simultaneous actions and hitherto unnoticed regulatory modules, such as the exemplified HIF1A that may directly act at UCP1 promoter, can set new direction in obesity research.HighlightsIntegrated pathways better characterize brown adipocytes than marker-genesDifferent processes shape the brown and white adipocyte phenotypesThermogenic phenotype may require simultaneous repression of whitening and induction of browningProtein network analyses reveals unnoticed regulatory modules of adipocyte phenotypeHIF1A may regulate thermogenesis by direct control of UCP1 gene-expressionGraphical Abstract

scholarly journals The Rosmarinus Bioactive Compound Carnosic Acid Is a Novel PPAR Antagonist That Inhibits the Browning of White Adipocytes

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2433
Author(s):  
Cécilia Colson ◽  
Pierre-Louis Batrow ◽  
Nadine Gautier ◽  
Nathalie Rochet ◽  
Gérard Ailhaud ◽  
...  
Keyword(s):  
Bioactive Compound ◽  
Antagonistic Effect ◽  
Carnosic Acid ◽  
Brown Adipocyte ◽  
Marker Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
White Adipocyte ◽  
White Adipocytes ◽  
And Function

Thermogenic brown and brite adipocytes convert chemical energy from nutrients into heat. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to control fat mass such as in obesity or cachexia. The peroxisome proliferator-activated receptor (PPAR) family plays key roles in the maintenance of adipose tissue and in the regulation of thermogenic activity. Activation of these receptors induce browning of white adipocyte. The purpose of this work was to characterize the role of carnosic acid (CA), a compound used in traditional medicine, in the control of brown/brite adipocyte formation and function. We used human multipotent adipose-derived stem (hMADS) cells differentiated into white or brite adipocytes. The expression of key marker genes was determined using RT-qPCR and western blotting. We show here that CA inhibits the browning of white adipocytes and favors decreased gene expression of thermogenic markers. CA treatment does not affect β-adrenergic response. Importantly, the effects of CA are fully reversible. We used transactivation assays to show that CA has a PPARα/γ antagonistic action. Our data pinpoint CA as a drug able to control PPAR activity through an antagonistic effect. These observations shed some light on the development of natural PPAR antagonists and their potential effects on thermogenic response.

scholarly journals Molecular Characterization, Protein-protein Interaction Network, and Evolution of four Glutathione Peroxidases from Tetrahymena Thermophila

2020 ◽  
Author(s):  
Diana Ferro ◽  
Rigers Bakiu ◽  
Sandra Pucciarelli ◽  
Cristina Miceli ◽  
Adriana Vallesi ◽  
...  
Keyword(s):  
Time Course ◽  
Tetrahymena Thermophila ◽  
Model Organism ◽  
Interaction Network ◽  
Regulatory Elements ◽  
Integrative Approach ◽  
Gene Characterization ◽  
Functional Relationships ◽  
Glutathione Peroxidases

Glutathione peroxidases (GPxs) form a broad family of antioxidant proteins essential for maintaining redox homeostasis in eukaryotic cells. In this study, we used an integrative approach that combines bioinformatics, molecular biology, and biochemistry to investigate the role of GPxs in reactive oxygen species detoxification in the unicellular eukaryotic model organism Tetrahymena thermophila. Both phylogenetic and mechanistic empirical model analyses provided indications about the evolutionary relationships among the GPXs of Tetrahymena and the orthologous enzymes of phylogenetically related species. In-silico gene characterization and text mining were used to predict the functional relationships between GPxs and other physiologically-relevant processes. The GPx genes contain conserved transcriptional regulatory elements in the promoter region, which suggest that transcription is under tight control of specialized signaling pathways. The bioinformatic findings were next experimentally validated by studying the time course of copper (Cu)-dependent regulation of gene transcription and enzymatic activity. Results emphasize the role of GPxs in the detoxification pathways that, by complex regulation of Cu-dependent GPx gene expression, enables Tetrahymena to survive in high Cu concentrations and the associated redox environment.

scholarly journals Molecular Characterization, Protein–Protein Interaction Network, and Evolution of Four Glutathione Peroxidases from Tetrahymena thermophila

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 949 ◽  
Author(s):  
Diana Ferro ◽  
Rigers Bakiu ◽  
Sandra Pucciarelli ◽  
Cristina Miceli ◽  
Adriana Vallesi ◽  
...  
Keyword(s):  
Time Course ◽  
Tetrahymena Thermophila ◽  
Model Organism ◽  
Interaction Network ◽  
Regulatory Elements ◽  
Integrative Approach ◽  
Gene Characterization ◽  
Functional Relationships ◽  
Glutathione Peroxidases

Glutathione peroxidases (GPxs) form a broad family of antioxidant proteins essential for maintaining redox homeostasis in eukaryotic cells. In this study, we used an integrative approach that combines bioinformatics, molecular biology, and biochemistry to investigate the role of GPxs in reactive oxygen species detoxification in the unicellular eukaryotic model organism Tetrahymena thermophila. Both phylogenetic and mechanistic empirical model analyses provided indications about the evolutionary relationships among the GPXs of Tetrahymena and the orthologous enzymes of phylogenetically related species. In-silico gene characterization and text mining were used to predict the functional relationships between GPxs and other physiologically-relevant processes. The GPx genes contain conserved transcriptional regulatory elements in the promoter region, which suggest that transcription is under tight control of specialized signaling pathways. The bioinformatic findings were next experimentally validated by studying the time course of gene transcription and enzymatic activity after copper (Cu) exposure. Results emphasize the role of GPxs in the detoxification pathways that, by complex regulation of GPx gene expression, enable Tethraymena to survive in high Cu concentrations and the associated redox environment.

scholarly journals Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anastasia Georgiadi ◽  
Valeria Lopez-Salazar ◽  
Rabih El- Merahbi ◽  
Rhoda Anane Karikari ◽  
Xiaochuan Ma ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Dependent Manner ◽  
Metabolic Dysfunction ◽  
Functional Interaction ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Obesity And Diabetes ◽  
Adhesion Gpcr ◽  
Circulating Levels

AbstractThe proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

scholarly journals Cissus Quadrangularis enhances UCP1 mRNA, indicative of white adipocyte browning and decreases central obesity in humans in a randomized trial

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Saimai Chatree ◽  
Chantacha Sitticharoon ◽  
Pailin Maikaew ◽  
Kitchaya Pongwattanapakin ◽  
Issarawan Keadkraichaiwat ◽  
...  
Keyword(s):  
Treated Group ◽  
Dependent Manner ◽  
Hip Circumference ◽  
White Adipocyte ◽  
Ppar Γ ◽  
White Adipocytes ◽  
Cissus Quadrangularis ◽  
Baseline Values ◽  
Dose Dependent ◽  
Vehicle Treated Group

AbstractObesity is associated with the growth and expansion of adipocytes which could be decreased via several mechanisms. Cissus Quadrangularis (CQ) extract has been shown to reduce obesity in humans; however, its effect on human white adipocytes (hWA) has not been elucidated. This study aimed to investigate the effects of CQ on obesity, lipolysis, and browning of hWA. CQ treatment in obese humans significantly decreased waist circumference at week 4 and week 8 when compared with the baseline values (p < 0.05 all) and significantly decreased hip circumference at week 8 when compared with the baseline and week 4 values (p < 0.05 all). Serum leptin levels of the CQ-treated group were significantly higher at week 8 compared to baseline levels (p < 0.05). In hWA, glycerol release was reduced in the CQ-treated group when compared with the vehicle-treated group. In the browning experiment, pioglitazone, the PPAR-γ agonist, increased UCP1 mRNA when compared to vehicle (p < 0.01). Interestingly, 10, 100, and 1000 ng/ml CQ extract treatment on hWA significantly enhanced UCP1 expression in a dose-dependent manner when compared to pioglitazone treatment (p < 0.001 all). In conclusion, CQ decreased waist and hip circumferences in obese humans and enhanced UCP1 mRNA in hWA suggestive of its action via browning of hWA.

scholarly journals E-cigarette Use and Respiratory Disorder: An Integrative Review of Converging Evidence from Epidemiological and Laboratory Studies

2020 ◽  
pp. 1901815
Author(s):  
Thomas A. Wills ◽  
Samir S. Soneji ◽  
Kelvin Choi ◽  
Ilona Jaspers ◽  
Elizabeth K. Tam
Keyword(s):  
Electronic Cigarettes ◽  
Meta Analysis ◽  
Epidemiological Studies ◽  
Chronic Obstructive ◽  
Human Populations ◽  
Respiratory Disorder ◽  
Biological Processes ◽  
Cigarette Use ◽  
Laboratory Studies ◽  
Consistency Strength

BackgroundUse of electronic cigarettes (e-cigarettes) is prevalent among adolescents and young adults but there has been limited knowledge about health consequences in human populations. We conduct a systematic review and meta-analysis of results on respiratory disorder from studies of general-population samples and consider the mapping of these results to findings about biological processes linked to e-cigarettes in controlled laboratory studies.MethodWe conduct a literature search and meta-analysis of epidemiological studies on the association of e-cigarette use with asthma and with chronic obstructive pulmonary disease (COPD). We then discuss findings from laboratory studies about effects of e-cigarettes on four biological processes: cytotoxicity, oxidative stress/inflammation, susceptibility to infection, and genetic expression.ResultsEpidemiological studies, both cross-sectional and longitudinal, show a significant association of e-cigarette use with asthma and COPD, controlling for cigarette smoking and other covariates. For asthma (n=15 studies), the pooled adjusted odds ratio (AOR) was 1.39 (CI 1.28–1.51); for COPD (n=9 studies) the AOR was 1.49 (CI 1.36–1.65). Laboratory studies consistently show an effect of e-cigarettes on biological processes related to respiratory harm and susceptibility to illness, with e-cigarette conditions differing significantly from clean-air controls though sometimes less than for cigarettes.ConclusionsThe evidence from epidemiological studies meets established criteria for consistency, strength of effect, temporality, and in some cases a dose-response gradient. Biological plausibility is indicated by evidence from multiple laboratory studies. We conclude that e-cigarette use has consequences for asthma and COPD, which is of significant concern for respirology and public health.

scholarly journals Limited Mitochondrial Capacity of Visceral Versus Subcutaneous White Adipocytes in Male C57BL/6N Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 923-933 ◽  
Author(s):  
Theresa Schöttl ◽  
Lisa Kappler ◽  
Katharina Braun ◽  
Tobias Fromme ◽  
Martin Klingenspor
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Mitochondrial Respiratory Chain ◽  
Metabolic Risk ◽  
Oxygen Species ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Fat Depot ◽  
Mitochondrial Capacity

Abstract Accumulation of visceral fat is associated with metabolic risk whereas excessive amounts of peripheral fat are considered less problematic. At the same time, altered white adipocyte mitochondrial bioenergetics has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. We therefore investigated whether the metabolic risk of visceral vs peripheral fat coincides with a difference in mitochondrial capacity of white adipocytes. We assessed bioenergetic parameters of subcutaneous inguinal and visceral epididymal white adipocytes from male C57BL/6N mice employing a comprehensive respirometry setup of intact and permeabilized adipocytes as well as isolated mitochondria. Inguinal adipocytes clearly featured a higher respiratory capacity attributable to increased mitochondrial respiratory chain content compared with epididymal adipocytes. The lower capacity of mitochondria from epididymal adipocytes was accompanied by an increased generation of reactive oxygen species per oxygen consumed. Feeding a high-fat diet (HFD) for 1 week reduced white adipocyte mitochondrial capacity, with stronger effects in epididymal when compared with inguinal adipocytes. This was accompanied by impaired body glucose homeostasis. Therefore, the limited bioenergetic performance combined with the proportionally higher generation of reactive oxygen species of visceral adipocytes could be seen as a candidate mechanism mediating the elevated metabolic risk associated with this fat depot.

scholarly journals Systems-level cancer gene identification from protein interaction network topology applied to melanogenesis-related functional genomics data

2009 ◽  
Vol 7 (44) ◽  
pp. 423-437 ◽  
Author(s):  
Tijana Milenković ◽  
Vesna Memišević ◽  
Anand K. Ganesan ◽  
Nataša Pržulj
Keyword(s):  
Protein Interaction ◽  
Network Topology ◽  
Interaction Network ◽  
Biological Processes ◽  
Cancer Gene ◽  
Cancer Genes ◽  
Clustering Methods ◽  
Ppi Network ◽  
Graph Theoretic ◽  
Ppi Networks

Many real-world phenomena have been described in terms of large networks. Networks have been invaluable models for the understanding of biological systems. Since proteins carry out most biological processes, we focus on analysing protein–protein interaction (PPI) networks. Proteins interact to perform a function. Thus, PPI networks reflect the interconnected nature of biological processes and analysing their structural properties could provide insights into biological function and disease. We have already demonstrated, by using a sensitive graph theoretic method for comparing topologies of node neighbourhoods called ‘graphlet degree signatures’, that proteins with similar surroundings in PPI networks tend to perform the same functions. Here, we explore whether the involvement of genes in cancer suggests the similarity of their topological ‘signatures’ as well. By applying a series of clustering methods to proteins' topological signature similarities, we demonstrate that the obtained clusters are significantly enriched with cancer genes. We apply this methodology to identify novel cancer gene candidates, validating 80 per cent of our predictions in the literature. We also validate predictions biologically by identifying cancer-related negative regulators of melanogenesis identified in our siRNA screen. This is encouraging, since we have done this solely from PPI network topology. We provide clear evidence that PPI network structure around cancer genes is different from the structure around non-cancer genes. Understanding the underlying principles of this phenomenon is an open question, with a potential for increasing our understanding of complex diseases.

scholarly journals An Effective Statistical Integrative Algorithm (Aeiapp) for Protein Prediction

2019 ◽  
Vol 8 (11) ◽  
pp. 132-137 ◽  
Keyword(s):  
Protein Interaction ◽  
Biological Networks ◽  
Protein Interaction Network ◽  
Protein Identification ◽  
Research Work ◽  
Interaction Network ◽  
Integrative Approach ◽  
Target Proteins ◽  
Protein Protein Interaction ◽  
Protein Protein Interaction Network

The task of predicting target proteins for new drug discovery is typically difficult. Target proteins are biologically most important to control a keen functional process. The recent research of experimental and computational -based approaches has been widely used to predict target proteins using biological networks analysis techniques. Perhaps with available methods and statistical algorithm needs to be modified and should be clearer to tag the main target. Meanwhile identifying wrong protein leads to unwanted molecular interaction and pharmacological activity. In this research work, a novel method to identify essential target proteins using integrative graph coloring algorithm has been proposed. The proposed integrative approach helps to extract essential proteins in protein-protein interaction network (PPI) by analyzing neighborhood of the active target protein. Experimental results reviewed based on protein-protein interaction network for homosapiens showed that AEIAPP based approach shows an improvement in the essential protein identification by assuming the source protein as biologically proven protein. The AEIAPP statistical model has been compared with other state of art approaches on human PPI for various diseases to produce good accurate outcome in faster manner with little memory consumption.

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