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Cited by 471Adipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and MetabolismCardiovascular Disease and Adiposity

Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity

Open access
Henegar, Corneliu, Tordjman, Joan, Achard, Vincent, Lacasa, Danièle, Cremer, Isabelle, Guerre-Millo, Michèle, Poitou, Christine, Basdevant, Arnaud +6 more·2008·Genome Biology
DOI 10.1186/gb-2008-9-1-r14PMC PMC2395253
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Abstract

Background: Investigations performed in mice and humans have acknowledged obesity as a low-grade inflammatory disease. Several molecular mechanisms have been convincingly shown to be involved in activating inflammatory processes and altering cell composition in white adipose tissue (WAT). However, the overall importance of these alterations, and their long-term impact on the metabolic functions of the WAT and on its morphology, remain unclear. Results: Here, we analyzed the transcriptomic signature of the subcutaneous WAT in obese human subjects, in stable weight conditions and after weight loss following bariatric surgery. An original integrative functional genomics approach was applied to quantify relations between relevant structural and functional themes annotating differentially expressed genes in order to construct a comprehensive map of transcriptional interactions defining the obese WAT. These analyses highlighted a significant up-regulation of genes and biological themes related to extracellular matrix (ECM) constituents, including members of the integrin family, and suggested that these elements could play a major mediating role in a chain of interactions that connect local inflammatory phenomena to the alteration of WAT metabolic functions in obese subjects. Tissue and cellular investigations, driven by the analysis of transcriptional interactions, revealed an increased amount of interstitial fibrosis in obese WAT, associated with an infiltration of different types of inflammatory cells, and suggest that phenotypic alterations of human pre-adipocytes, induced by a pro-inflammatory environment, may lead to an excessive synthesis of ECM components. Conclusion: This study opens new perspectives in understanding the biology of human WAT and its pathologic changes indicative of tissue deterioration associated with the development of obesity.

AI snapshot

Written from the paper’s full text.

TL;DR

In subcutaneous white adipose tissue from obese humans, transcriptomic analysis revealed a segregated signature linking extracellular matrix/inflammatory processes in the stroma-vascular fraction with down-regulated intracellular metabolic/apoptotic processes in mature adipocytes. Histology confirmed increased interstitial fibrosis in obese WAT that persisted three months after bariatric surgery, and macrophage-conditioned medium induced ECM production by pre-adipocytes.

Key findings

  • In 35 cDNA microarrays from 25 weight-stable obese subjects (BMI 40.58 ± 1.58 kg/m²) and 10 lean controls (BMI 23.67 ± 0.48 kg/m²), SAM detected 366 up- and 474 down-regulated genes at 5% FDR; up-regulated genes were annotated mainly to membrane/extracellular/immune/inflammatory themes, while down-regulated genes were annotated to intracellular, lipid/energy metabolism, and apoptosis themes.
  • Two segregated interaction modules were identified: module 1 grouped ECM, inflammatory, cell adhesion, and signaling themes and was enriched in genes expressed predominantly in the stroma-vascular fraction; module 2 grouped intracellular metabolic, mitochondrial, ribosomal, and apoptotic themes and was enriched in genes expressed predominantly in mature adipocytes. Among over-represented GO categories, 40 ECM-related genes (12.5%; 24 up-regulated and 16 down-regulated) were found.
  • Subcutaneous WAT fibrosis was significantly higher in obese subjects than lean controls (6.29% ± 2 versus 2.19% ± 0.25, p < 0.05) and remained high three months after bariatric surgery (5.7% ± 1.63); patients with the highest hepatic fibrosis score also had more WAT fibrosis (p < 0.05).
  • After gastric bypass, 10 cDNA microarrays showed 1,744 up- and 1,627 down-regulated genes at 5% FDR, with up-regulated oxidative phosphorylation/mitochondrial and glycan-degradation pathways and down-regulated immune/inflammatory/signaling/ECM themes; in pre-adipocytes treated with activated macrophage-conditioned medium, >5,200 genes were up-regulated, 71.4% of ECM-related genes changed in obese WAT also changed in vitro, 60% shared the same direction (p < 0.05), and TGF-beta showed a 2.5-fold increase (p < 0.05).

Methods

  • Prospective recruitment included 55 obese subjects and 15 lean controls; 35 cDNA microarrays compared subcutaneous WAT from 25 weight-stable obese subjects and 10 lean controls, 10 paired arrays compared WAT before and three months after laparoscopic gastric bypass, fraction-comparison arrays used subcutaneous WAT from 9 overweight women, and 8 arrays tested human pre-adipocytes cultured with activated macrophage-conditioned media. Raw data were deposited in GEO (GSE9157).
  • Differential expression used print-tip loess normalization and SAM at a 5% FDR; functional annotation used GO and KEGG over-representation, transcriptomic interaction maps were built by quantifying expression similarity between annotated themes and clustering with spectral methods, and gene co-expression networks used Spearman’s correlation with an absolute Rs ≥ 0.8 threshold plus centrality measures.
  • Tissue and cellular validation included morphometry, picrosirius red fibrosis quantification, CD3/NKp46 immunohistochemistry, electron microscopy, liver histopathology, RTqPCR, and immunofluorescence for collagen type I and fibronectin in pre-adipocytes.

Limitations

  • The paper states that enzymatic digestion used to separate adipocytes and SVF cells may influence their expression profiles, that the precise phenotype of macrophages in human WAT is still unknown, that other SVF cell types such as myofibroblasts or fibroblasts need further characterization, and that WAT fibrosis may be irreversible or may take more than three months to resolve after weight loss.
  • Evident from the text: several substudies rely on small samples (10 obese subjects before/after surgery, 10 lean controls for fibrosis, 5 women for pre-adipocyte culture, 9 overweight women for fraction arrays), and the design is observational/correlational, so causal direction is not established.
  • Evident from the text: the main findings are microarray-based and require further mechanistic validation, although selected genes were assessed by RTqPCR and cellular/histological follow-up.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/gb-2008-9-1-r14

Cites

87 of 87 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 59 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Subcutaneous white adipose tissue of obese human subjects is characterized by increased/excessive interstitial fibrosis.

    “Analysis of the transcriptomic signature of white adipose tissue in obese human subjects revealed increased interstitial fibrosis and an infiltration of inflammatory cells into the tissue.”
    • Also stated in: § Background · plain
      “Tissue and cellular investigations, directed by the hypotheses raised by the analysis of gene and functional interactions, show that subcutaneous adipose tissue of obese subjects is characterized by an excessive amount of interstitial fibrosis”
    Quote in the paperSubstantial claim
  • Findingown data

    Analysis of the transcriptomic signature of white adipose tissue in obese human subjects revealed infiltration of inflammatory cells into the tissue.

    “Analysis of the transcriptomic signature of white adipose tissue in obese human subjects revealed increased interstitial fibrosis and an infiltration of inflammatory cells into the tissue.”
    Quote in the paperSubstantial claim
  • Findingown data

    HSPA8 was significantly co-expressed with integrin alpha V, annexin I and other ECM components.

    “Also, the heat shock protein 8 (HSPA8), a surface marker for the undifferentiated cellular state expressed on the surface of human embryonic stem cells [39], performs an important role in the repair processes following harmful tissular assaults (for example, hemorrhage or local ischemia) [40], and was found to be significantly co-expressed with integrin alpha V, annexin I and other ECM components.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [39] Son YS, Park JH, Kang YK, Park JS, Choi HS, Lim JY, Lee JE, Lee JB, Ko MS, Kim YS, Kob JH, Yoonc HS, Leed KW, Seongd RH, Moonf SY, Ryua CJ, Hong HJ: Heat shock 70-kDa protein 8 isoform 1 is expressed on the surface of human embryonic stem cells and downregulated upon differentiation. Stem Cells. 2005, 23: 1502-1513. 10.1634/stemcells.2004-0307. source

      Not checked in the free run.

    • cites [40] Kiang JG: Inducible heat shock protein 70 kD and inducible nitric oxide synthase in hemorrhage/resuscitation-induced injury. Cell Res. 2004, 14: 450-459. 10.1038/sj.cr.7290247. source

      Not checked in the free run.

  • Findingown data

    The analysis uncovered a highly segregated transcriptomic interaction pattern, regardless of the system used to annotate differentially expressed genes.

    “This analysis uncovered a highly segregated transcriptomic interaction pattern, regardless of the system used to annotate differentially expressed genes (Figures 1b, 2b and 3b).”
    Quote in the paperSubstantial claim
  • Findingown data

    Numerous components of cytoplasmic or mitochondrial ribosomal subunits showed significant negative correlations with BMI, including RPL28, RPS12, RPL35, RPS2, and RPS21.

    “Also, the expression profiles of numerous components of cytoplasmic or mitochondrial ribosomal subunits showed significant negative correlations with the BMI (RPL28, RPS12, RPL35, RPS2, and RPS21 among others).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 43
  • The quote only partly states this claim. 5
  • Classified as probably not a substantial claim. 38

  • May combine two claims.

    Findingown data

    Several genes coding for members of the integrin family were significantly induced and co-expressed in obese WAT, occupying central positions in the first co-expression module.

    “Among various ECM components, several genes coding for members of the integrin family were found to be significantly induced and co-expressed in obese WAT, occupying central positions in the first co-expression module (Figure 4, module 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genes up-regulated in obese WAT were annotated mainly by structural and functional themes associated with the cellular membrane and the extracellular space, while down-regulated genes were annotated mostly by themes related to the intracellular domain.

    “While the genes up-regulated in the obese WAT were annotated mainly by structural and functional themes associated with the cellular membrane and the extracellular space, the down-regulated genes were annotated mostly by themes related to the intracellular domain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Functional analysis identified 704 genes (307 up- and 397 down-regulated) annotated with GO categories, and 253 genes (101 up- and 152 down-regulated) annotated with KEGG categories.

    “The functional analysis of these genes identified 704 genes (307 up- and 397 down-regulated) annotated with Gene Ontology (GO) categories [22], and 253 genes (101 up- and 152 down-regulated) annotated with categories of the Kyoto Encyclopedia of Genes and Genomes (KEGG) [23].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Gene Ontology. [http://www.geneontology.org]

      Not checked in the free run.

    • cites [23] Kyoto Encyclopedia of Genes and Genomes. [http://www.genome.jp/kegg/]

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The expression levels of CPT1A and CPT1B were decreased, as well as that of the CRAT gene, in obese WAT.

    “The expression levels of two members of the carnitine/choline acetyltransferase family (CPT1A and CPT1B) involved in this rate limiting step across the mitochondrial inner membrane were decreased as well as that of the CRAT gene, which catalyzes the reversible transfer of acyl groups from an acyl-CoA thioester to carnitine and regulates the ratio of acylCoA/CoA in the mitochondrial compartments.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Module 2 gathered several genes involved in induction of apoptosis, such as DAP, DAPK2, STK17A, SIVA1, TRADD, and PDCD5, some being strongly co-expressed with mitochondrial enzymes.

    “Interestingly, module 2 also gathered several genes involved in the induction of apoptosis, such as the death-associated protein (DAP), the death-associated protein kinase 2 (DAPK2), and the serine/threonine kinase 17a (STK17A), a member of the DAP kinase-related apoptosis-inducing protein kinase family, as well as the apoptosis-inducing factor (SIVA1), TNFRSF1A-associated via death domain (TRADD)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Our analysis revealed major and interrelated changes of WAT transcriptomic signature in obese human subjects, involving extracellular matrix (ECM), and inflammatory and adipose metabolic processes.

    “Our analysis revealed major and interrelated changes of WAT transcriptomic signature in obese human subjects, involving extracellular matrix (ECM), and inflammatory and adipose metabolic processes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A number of these genes showed significant co-expression with members of the integrin family and are known to be involved in the recruitment and activation of immune circulating cells, such as monocytes, lymphocytes or neutrophils.

    “A number of these genes showed significant co-expression with members of the integrin family and are known to be involved in the recruitment and activation of immune circulating cells, such as monocytes, lymphocytes or neutrophils.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In obese WAT, some ECM-related genes are co-expressed with inflammatory genes (module 1) and show a significant inverse expression pattern to genes belonging to the metabolic module (module 2).

    “As shown in Figure 4, some ECM related genes were co-expressed with a set of inflammatory genes (module 1), while showing a significant inverse expression pattern to that of genes belonging to the metabolic module (module 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Biological themes related to the extracellular space (module 1) annotated genes predominantly expressed in the SVF of WAT, while genes annotated with themes related to the intracellular domain (module 2) were expressed predominantly in mature adipocytes.

    “This analysis showed that biological themes related to the extracellular space (module 1) were annotating genes predominantly expressed in the SVF of WAT, while the genes annotated with themes related to the intracellular domain (module 2) were expressed predominantly in mature adipocytes (Figures 1b, 2b and 3b).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In obese WAT, ITGAV, CD163, CCL18, HSPA8, and CNTNAP1 are strongly related to several genes encoding lipolytic pathway enzymes including LIPE, PLIN, and PAP2B, and to apoptosis-related genes DAPK2 and NME3.

    “Among them, integrin alpha V (ITGAV), CD163 and CCL18, two markers of the alternative pathway of macrophage activation, heat shock protein 8 (HSPA8), and contactin associated protein 1 (CNTNAP1), involved in the activation of intracellular signaling pathways, were strongly related to several genes encoding enzymes of the lipolytic pathway”
    • Also stated in: § The transcriptomic signature of the subcutaneous WAT in obese subjects · plain
      “and to genes related to apoptosis, such as death-associated protein kinase 2 (DAPK2) and non-metastatic cells 3 protein (NME3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two distinct types of biological interaction modules were identified: module 1 associating structural components, processes and regulatory pathways related to cellular membranes and the extracellular space, and module 2 grouping components, processes and pathways associated with the intracellular domain.

    “Two distinct types of biological interaction modules (indicated hereafter as module 1 and module 2) have been identified, one associating structural components, processes and regulatory pathways related to cellular membranes and the extracellular space (module 1), while the other groups components, processes and pathways associated with the intracellular domain (module 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Functional analysis identified 2,687 genes (1,390 up- and 1,297 down-regulated) annotated with GO categories and 868 genes (450 up- and 418 down-regulated) annotated with KEGG categories.

    “Functional analysis of these genes identified 2,687 genes (1,390 up- and 1,297 down-regulated) annotated with GO categories, and 868 genes (450 up- and 418 down-regulated) annotated with KEGG categories.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The analysis highlighted a segregated transcriptomic interaction pattern in obese WAT, distinguishing two interaction modules: module 1 grouping inflammatory and ECM related processes and module 2 associating adipose metabolic functions and other themes related to apoptosis and protein synthesis processes.

    “This analysis also highlighted a segregated transcriptomic interaction pattern in obese WAT, distinguishing two interaction modules: one (module 1) grouping inflammatory and ECM related processes and another (module 2) associating adipose metabolic functions and other themes related to apoptosis and protein synthesis processes.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In pre-adipocytes treated by AcMC medium, genes grouped in these functions included representatives from all classes of ECM components, including structural proteins, adherent proteins, glycosaminoglycans, proteoglycans, specialized glycoproteins, integrins, and ECM remodeling enzymes and TIMP1.

    “The examination of the genes grouped in these functions retrieved representatives from all classes of ECM components, such as structural proteins, including members of the collagen family and several precursors of collagen formation, adherent proteins, such as fibronectin 1 and its receptor, as well as laminin family members, glycosaminoglycans and proteoglycans (lumican (LUM)), and specialized”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Companion Website to this Study. [http://corneliu.henegar.info/projects/FunNet/genome_biol_2008/index.htm]

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Sixty percent of these ECM-related genes demonstrated a similar variation of expression patterns in both in vivo and in vitro conditions, a proportion significantly greater (p < 0.05) than the overall percentage of genes sharing similar expression patterns among those demonstrating significant differential expression in the human and cell studies.

    “Sixty percent of these ECM-related genes demonstrated a similar variation of their expression patterns in both in vivo and in vitro conditions, a proportion significantly greater (p value < 0.05) than the overall percentage of genes sharing similar expression patterns among those demonstrating a significant differential expression in the human and cell studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Associated with the down-regulation of genes coding for inflammation mediators, an important number of genes related to oxidative phosphorylation and various other mitochondrial enzymes, as well as genes coding for enzymes involved in the degradation of glycosaminoglycans and proteoglycans, registered a significantly increased expression after weight loss.

    “Associated with the down-regulation of genes coding for inflammation mediators, an important number of genes related to oxidative phosphorylation and various other mitochondrial enzymes, as well as genes coding for enzymes involved in the degradation of glycosaminoglycans and proteoglycans, registered a significantly increased expression after weight loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Three months after gastric bypass, the majority of up-regulated WAT genes were associated with structural themes related to the intracellular domain and organelles, while down-regulated genes were mostly associated with cellular membrane and extracellular space themes.

    “Indeed, the majority of the genes up-regulated in WAT after gastric bypass were associated with structural themes (GO Cellular Component) related to the intracellular domain and organelles ('protein complex', 'cytoplasm', 'mitochondrion', 'endoplasmic reticulum', 'lysosome', 'actin cytoskeleton', 'cytosolic part'), while the down-regulated genes (Figure 8a) were mostly associated with cellular”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Matrix metallopeptidase 2 (MMP2) and tissue inhibitor of metalloproteinase family members TIMP1 and TIMP2 were induced after weight loss.

    “In addition, some metallopeptidases implicated in the degradation of other ECM components were equally induced, such as the matrix metallopeptidase 2 (MMP2), concomitantly with several metallopeptidase inhibitors from the tissue inhibitor of metalloproteinase family (TIMP1, TIMP2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    A number of ECM components showed opposite expression patterns to those noted in the previous condition, some being induced by weight loss while others were down-regulated.

    “A number of ECM components showed opposite expression patterns to those noted in the previous condition, some being induced by weight loss while others were down-regulated (online supplementary Table 2 [20]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Companion Website to this Study. [http://corneliu.henegar.info/projects/FunNet/genome_biol_2008/index.htm]

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Fibrosis quantification in the same subjects three months after bariatric surgery found no significant decrease of interstitial fibrosis, in spite of a significant down-regulation of genes related to inflammatory and immune responses and extensive variations in expression of genes involved in ECM remodeling.

    “Ffibrosis quantification in the same subjects three months after bariatric surgery found no significant decrease of interstitial fibrosis, in spite of a significant down-regulation of the genes related to inflammatory and immune responses and extensive variations in the expression of genes involved in ECM remodeling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Surgery-induced weight loss was associated with a major shift of the WAT regulatory and interaction patterns, which reversed the functional genomic profile of the obese WAT and dramatically increased the intensity of the interactions between up-regulated adipose metabolic processes and down-regulated inflammatory and immune responses.

    “Interestingly, the surgery induced weight loss was associated with a major shift of the WAT regulatory and interaction patterns, which reversed the functional genomic profile of the obese WAT and dramatically increased the intensity of the interactions between up-regulated adipose metabolic processes and down-regulated inflammatory and immune responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A significant fraction of the genes composing module 1 were positively correlated with BMI, while most of the genes grouped in module 2 showed negative correlation with the degree of obesity.

    “This segregated interaction pattern was also confirmed by the observation that a significant fraction of the genes composing module 1 were positively correlated with BMI, while most of the genes grouped in module 2 showed negative correlation with the degree of obesity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    We observed the presence of NK and T lymphocytes in obese WAT, although they appeared to be less abundant than macrophage cells.

    “We observed the presence of NK and T lymphocytes in obese WAT, although they appeared to be less abundant than macrophage cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    IL13RA1 and the IL4 receptor were induced in pre-adipocytes treated by AcMC-conditioned media.

    “Among them, we noted the induction of IL13RA1, a subunit of the IL13 receptor complex reported to play a role in the internalization of IL13, and a major profibrotic protein known to induce transforming growth factor beta, and also of the IL4 receptor, which binds IL13 and IL4 and represents another well recognized profibrotic cytokine.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Human pre-adipocytes cultured in the presence of AcMCs increased their production of fibronectin and collagen type I, which formed a fibrous network around the pre-adipocytes.

    “In agreement, human pre-adipocytes cultured in the presence of AcMCs increased their production of fibronectin and collagen type I, which formed a fibrous network around the pre-adipocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Collagen type I and fibronectin were over-expressed in AcMC-conditioned media and organized in a fiber network structure in pre-adipocytes.

    “Collagen type I and fibronectin were over-expressed in AcMC-conditioned media and organized in a fiber network structure (Figure 14a-d).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisenone given

    The relationship between these genes, the cellular processes in which they are involved, and the tissue structure as a whole remains poorly understood.

    “However, the relationship between these genes, the cellular processes in which they are involved, and the tissue structure as a whole remains poorly understood.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CCL18 is involved in recruitment and activation of CD4+ and CD8+ T cells and plays a central role in perpetuating fibrotic processes through a positive feedback loop linking activated macrophages to fibroblasts.

    “CCL18 is also known to be involved in the recruitment and activation of CD4+ and CD8+ T cells and, more remarkably, is credited with playing a central role in perpetuating fibrotic processes through its involvement in a positive feedback loop that links activated macrophages to fibroblasts [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Prasse A, Pechkovsky DV, Toews GB, Jungraithmayr W, Kollert F, Goldmann T, Vollmer E, Muller-Quernheim J, Zissel G: A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18. Am J Respir Crit Care Med. 2006, 173: 781-792. 10.1164/rccm.200509-1518OC. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HIF1A is a transcription factor that performs an essential role in cellular responses to hypoxia, is involved in regulation of macrophage migration, and modulates metabolism of immune cells exposed to low oxygen tensions in hypoxic areas of inflamed tissues.

    “Co-expressed with Mac-1 components, the hypoxia-inducible factor 1 (HIF1A) is a well characterized transcription factor that performs an essential role in cellular responses to hypoxia. HIF1A is also involved in the regulation of macrophage migration, and modulates the metabolism of immune cells exposed to low oxygen tensions in hypoxic areas of inflamed tissues [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Sitkovsky M, Lukashev D: Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat Rev Immunol. 2005, 5: 712-721. 10.1038/nri1685. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weight loss is associated with improvement in the inflammatory profile and regression of macrophage infiltration in WAT.

    “We have shown previously that weight loss is associated with improvement in the inflammatory profile, together with regression of macrophage infiltration in WAT [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Clement K, Viguerie N, Poitou C, Carette C, Pelloux V, Curat CA, Sicard A, Rome S, Benis A, Zucker JD, Vidal H, Laville M, Barsh GS, Basdevant A, Štich V, Stich V, Cancello R, Langin D: Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J. 2004, 18: 1657-1669. 10.1096/fj.04-2204com. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CCL18 synthesis by alternatively activated macrophages is induced by Th2 cytokines, ITGB2 and CD163.

    “Available data demonstrate that the synthesis of CCL18 by alternatively activated macrophages is induced by Th2 cytokines, integrin beta 2 (ITGB2) and the scavenger receptor (CD163) [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Prasse A, Pechkovsky DV, Toews GB, Jungraithmayr W, Kollert F, Goldmann T, Vollmer E, Muller-Quernheim J, Zissel G: A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18. Am J Respir Crit Care Med. 2006, 173: 781-792. 10.1164/rccm.200509-1518OC. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Elevated inflammatory proteins in obese individuals suggest that inflammation may play a determinant role in connecting obesity to metabolic, hepatic and cardiovascular diseases, and to some cancers.

    “Elevated inflammatory proteins in obese individuals [1] suggest that inflammation may play a determinant role in connecting obesity to metabolic, hepatic and cardiovascular diseases [2], and to some cancers [3].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Ridker PM, Buring JE, Cook NR, Rifai N: C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003, 107: 391-397. 10.1161/01.CIR.0000055014.62083.05. source

      Not checked in the free run.

    • cites [2] Hotamisligil GS: Inflammation and metabolic disorders. Nature. 2006, 444: 860-867. 10.1038/nature05485. source

      Not checked in the free run.

    • cites [3] Hursting SD, Nunez NP, Varticovski L, Vinson C: The obesity-cancer link: lessons learned from a fatless mouse. Cancer Res. 2007, 67: 2391-2393. 10.1158/0008-5472.CAN-06-4237. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The molecular mechanisms that link inflammatory changes to the development, aggravation, maintenance, and resistance to treatment that characterize obesity states remain poorly understood.

    “However, in spite of substantial evidence demonstrating the existence of a low-grade inflammatory component in obesity [5], the molecular mechanisms that link inflammatory changes to the development, aggravation, maintenance, and resistance to treatment that characterize obesity states remain poorly understood.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Cottam DR, Mattar SG, Barinas-Mitchell E, Eid G, Kuller L, Kelley DE, Schauer PR: The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. Obes Surg. 2004, 14: 589-600. 10.1381/096089204323093345. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    In obese human subjects, large-scale transcriptomic analyses of WAT led mostly to description of inflammatory changes and produced extensive lists of regulated genes involved in a number of biological functions.

    “In obese human subjects, large-scale transcriptomic analyses of WAT, in stable weight conditions or during weight loss, led mostly to the description of inflammatory changes and produced extensive lists of regulated genes involved in a number of biological functions [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Viguerie N, Poitou C, Cancello R, Stich V, Clement K, Langin D: Transcriptomics applied to obesity and caloric restriction. Biochimie. 2005, 87: 117-123. 10.1016/j.biochi.2004.12.011. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Phenotypic changes in human pre-adipocytes, induced by a pro-inflammatory environment, are associated with excessive synthesis of ECM components, which may contribute to tissue deterioration.

    “suggest that the phenotypic changes in human pre-adipocytes, induced by a pro-inflammatory environment, are associated with excessive synthesis of ECM components, which may contribute to tissue deterioration.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Adipose loss leads to improvement of the inflammatory profile, with a concomitant reduction of infiltrating macrophages.

    “Adipose loss leads to the improvement of the inflammatory profile [11], with a concomitant reduction of infiltrating macrophages [13].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Clement K, Viguerie N, Poitou C, Carette C, Pelloux V, Curat CA, Sicard A, Rome S, Benis A, Zucker JD, Vidal H, Laville M, Barsh GS, Basdevant A, Štich V, Stich V, Cancello R, Langin D: Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J. 2004, 18: 1657-1669. 10.1096/fj.04-2204com. source

      Not checked in the free run.

    • cites [13] Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumié A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clément K: Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes. 2005, 54: 2277-2286. 10.2337/diabetes.54.8.2277. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The non-adipose stroma vascular fraction (SVF) of WAT, comprising infiltrated macrophages among other cellular types, is a source of inflammation-related molecules that may exert a local action on adipose tissue biology, particularly within the enlarged WAT.

    “Although some molecules secreted by WAT, such as leptin and adiponectin, are synthesized by mature adipocytes [8], the non-adipose SVF, comprising infiltrated macrophages among other cellular types, is a source of inflammation-related molecules that may exert a local action on adipose tissue biology, particularly within the enlarged WAT [9-11].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003, 112: 1821-1830. 10.1172/JCI200319451. source

      Not checked in the free run.

    • cites [10] Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R, Bouloumie A: From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes. 2004, 53: 1285-1292. 10.2337/diabetes.53.5.1285. source

      Not checked in the free run.

    • cites [11] Clement K, Viguerie N, Poitou C, Carette C, Pelloux V, Curat CA, Sicard A, Rome S, Benis A, Zucker JD, Vidal H, Laville M, Barsh GS, Basdevant A, Štich V, Stich V, Cancello R, Langin D: Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J. 2004, 18: 1657-1669. 10.1096/fj.04-2204com. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    White adipose tissue contributes to systemic inflammation by producing biomolecules, including pro-inflammatory mediators, whose synthesis is altered along with expansion of the adipose tissue.

    “White adipose tissue (WAT), now considered as a pivotal endocrine organ, contributes to the systemic inflammation by producing biomolecules, including pro-inflammatory mediators, whose estimated number grows constantly and whose synthesis is altered along with the expansion of the adipose tissue [6,7].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Ailhaud G: Adipose tissue as an endocrine organ. Int J Obes Relat Metab Disord. 2000, 24 (Suppl 2): S1-3. source

      Not checked in the free run.

    • cites [7] Lyon CJ, Law RE, Hsueh WA: Minireview: adiposity, inflammation, and atherogenesis. Endocrinology. 2003, 144: 2195-2200. 10.1210/en.2003-0285. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent data provided by our team showed that human pre-adipocytes in contact with activated macrophage media display a fibroblastic-like appearance, significantly proliferate and acquire pro-inflammatory properties.

    “Recent data provided by our team showed that human pre-adipocytes in contact with activated macrophage media display a fibroblastic-like appearance, significantly proliferate and acquire pro-inflammatory properties [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Lacasa D, Taleb S, Keophiphath M, Miranville A, Clement K: Macrophage-secreted factors impair human adipogenesis: involvement of pro-inflammatory state in pre-adipocytes. Endocrinology. 2007, 148: 868-877. 10.1210/en.2006-0687. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Our study of functional profiles and transcriptomic interactions characterizing the adipose tissue of subjects in the obese static phase confirms the strong relationship linking inflammatory processes and ECM remodeling, associated with different inflammatory cell types and to some degree of interstitial fibrosis in WAT.

    “Our study of functional profiles and transcriptomic interactions characterizing the adipose tissue of subjects in the obese static phase confirm the strong relationship linking inflammatory processes and ECM remodeling, associated with different inflammatory cell types and to some degree of interstitial fibrosis in WAT.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A relationship between lymphocyte count and the weight of visceral and subcutaneous fat pads was also noted.

    “A relationship between lymphocyte count and the weight of visceral and subcutaneous fat pads was also noted [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Caspar-Bauguil S, Cousin B, Andre M, Nibbelink M, Galinier A, Periquet B, Casteilla L, Penicaud L: Weight-dependent changes of immune system in adipose tissue: importance of leptin. Exp Cell Res. 2006, 312: 2195-2202. 10.1016/j.yexcr.2006.03.023. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In obese mice, a shift in the activation state of WAT macrophages from an M2 'alternatively activated' state to an M1 'pro-inflammatory state' was observed in response to diet-induced obesity.

    “In obese mice, a shift in the activation state of WAT macrophages from an M2 'alternatively activated' state to an M1 'pro-inflammatory state' was observed in response to diet-induced obesity [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Lumeng CN, Bodzin JL, Saltiel AR: Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007, 117: 175-184. 10.1172/JCI29881. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    To date, only a few comparative studies have described the lymphoid accumulation in WAT of obese subjects.

    “To date, only a few comparative studies have described the lymphoid accumulation in WAT of obese subjects [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Marti A, Marcos A, Martinez JA: Obesity and immune function relationships. Obes Rev. 2001, 2: 131-140. 10.1046/j.1467-789x.2001.00025.x. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Human obesity can be considered as a set of phenotypes that develop successively over time, distinguishing a pre-obese static phase, a dynamic weight gain phase, and an obese static phase.

    “From a temporal perspective, human obesity can be considered as a set of phenotypes that develop successively over time. In this sequence one can distinguish: a 'pre-obese static phase' when the individual at risk of obesity has a stable weight and energy balance status; a 'dynamic weight gain phase' during which weight increases as a result of a positive energy balance with intakes exceeding”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Obesity: Preventing and Managing the Global Epidemic. Report of a WHO Consultation. World Health Organ Tech Rep Ser. 2000, 894: i-xii. 1-253.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In fibrotic diseases, accumulation of ECM components can be driven primarily by inflammatory processes.

    “In fibrotic diseases it has been shown that the accumulation of ECM components can be driven primarily by inflammatory processes [59].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Iredale JP: Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest. 2007, 117: 539-548. 10.1172/JCI30542. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The co-expression network analysis showed a concomitant up-regulation of genes related to both matrix metalloproteinase and tissue inhibitor of metalloproteinase families, which could explain the reduced degradation of ECM components after weight loss.

    “The co-expression network analysis showed a concomitant up-regulation of genes related to both matrix metalloproteinase and tissue inhibitor of metalloproteinase families (online supplementary Table 2 [20]), which could explain the reduced degradation of ECM components after weight loss.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Companion Website to this Study. [http://corneliu.henegar.info/projects/FunNet/genome_biol_2008/index.htm]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationown data

    This may be associated with the presence of M1 macrophages, since genes encoding pro-inflammatory factors were also induced.

    “This may be associated with the presence of M1 macrophages, since genes encoding pro-inflammatory factors were also induced.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Interpretationreasoning

    Examination of the functional interaction networks indicated that a phenomenon similar to excessive ECM synthesis and deposition in chronic inflammatory diseases may occur in obese WAT, involving inflammatory cells and a possible contribution by fibroblast-derived pre-adipocytes in producing ECM components.

    “Examination of the functional interaction networks indicated that a similar phenomenon may occur in the obese WAT, involving the presence of inflammatory cells and a possible contribution by fibroblast derived pre-adipocytes in producing ECM components.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In chronic low-grade inflammatory diseases, prolonged inflammation stimuli result in tissue injuries that can lead to excessive synthesis of ECM elements and their progressive deposition.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the initial phase, behavioral and environmental factors could play a key role in the constitution of adipose tissue excess on a genetically predisposed background.

    “In the initial phase, behavioral and environmental factors could play a key role in the constitution of adipose tissue excess on a genetically predisposed background [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Mutch DM, Clement K: Unraveling the genetics of human obesity. PLoS Genet. 2006, 2: e188-10.1371/journal.pgen.0020188. source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationown data

    Both our functional analysis and cellular studies indicate that a pathological process similar to excessive ECM production and accumulation might occur in obese WAT.

    “Both our functional analysis and cellular studies indicate that such a pathological process might occur in obese WAT.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Persistence of tissue injuries can lead over time to an excessive production of ECM components, which accumulate progressively and may result eventually in impaired tissular function.

  • May combine two claims.

    Interpretationown data

    The full-scale exploratory analysis of the obese WAT transcriptomic signature highlights the central place occupied by inflammatory and immune processes and shows strong interaction with ECM components grouped in the same module (module 1).

    “Our full-scale exploratory analysis of the obese WAT transcriptomic signature highlights the central place occupied by inflammatory and immune processes and shows the strong interaction with ECM components grouped in the same module (module 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These results do not exclude the role of mature adipocytes in the excessive synthesis of some ECM components.

    “However, these results do not exclude the role of mature adipocytes in the excessive synthesis of some ECM components.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Fibrosis may be more than a passive witness of the pathologic state of the tissue, possibly indicating a degree of irreversibility in the evolution of obesity, as seems to be suggested by its persistence after a drastic decrease of the adipose mass, in spite of the regression of the local inflammatory phenomena.

    “Fibrosis may be more than a passive witness of the pathologic state of the tissue, possibly indicating a degree of irreversibility in the evolution of obesity, as seems to be suggested by its persistence after a drastic decrease of the adipose mass, in spite of the regression of the local inflammatory phenomena.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Once the obese phase is attained, the new weight status appears to be strongly defended by both biological and psychological regulatory mechanisms.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Major histopathological features were recorded and semi-quantified according to previously published criteria.

    “Major histopathological features were recorded and semi-quantified according to previously published criteria [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ, Nonalcoholic Steatohepatitis Clinical Research Network: Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005, 41: 1313-1321. 10.1002/hep.20701. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The gene expression changes were validated by reverse transcription and RTqPCR.

    “We validated the gene expression changes by reverse transcription and RTqPCR, performed as described in [63].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Clement K, Viguerie N, Diehn M, Alizadeh A, Barbe P, Thalamas C, Storey JD, Brown PO, Barsh GS, Langin D: In vivo regulation of human skeletal muscle gene expression by thyroid hormone. Genome Res. 2002, 12: 281-291. 10.1101/gr.207702. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Slides were coded and analyzed by a single expert pathologist blind to the identity of the biopsy.

    “Slides were coded and analyzed by a single expert pathologist blind to the identity of the biopsy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Thin sections were haematoxylin-eosin stained and analyzed by three independent observers in a blind fashion.

    “Thin sections (5 μm thick) were haematoxylin-eosin stained and analyzed by three independent observers in a blind fashion with a Zeiss 20 Axiostar Plus microscope (Zeiss, Germany).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Several quality cross-checks (for total RNA quality, aRNA quality, dye incorporation efficiency, and so on) and microarray 'dye swap' experiments were performed.

    “Several quality cross-checks (for total RNA quality, aRNA quality, dye incorporation efficiency, and so on) and microarray 'dye swap' experiments were also performed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    EntrezGene numbers were used as a standard transcript accession system to ensure a correct over-representation analysis, as they allow mapping of gene identifiers to GO or KEGG biological categories.

    “EntrezGene numbers [72] were used as a standard transcript accession system to ensure a correct over-representation analysis, as they allow one to map gene identifiers to GO or KEGG biological categories.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Maglott D, Ostell J, Pruitt KD, Tatusova T: Entrez Gene: gene-centered information at NCBI. Nucleic Acids Res. 2007, 35: D26-31. 10.1093/nar/gkl993. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    There was no significant difference in age between obese subjects and lean controls.

    “There was no significant difference in terms of age between obese subjects and lean controls.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All clinical investigations were performed according to the Declaration of Helsinki and were approved by the Ethics Committees of Hôtel-Dieu hospital (Paris, France).

    “All clinical investigations were performed according to the Declaration of Helsinki and were approved by the Ethics Committees of Hôtel-Dieu hospital (Paris, France).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Regardless of the actual mechanism explaining its persistence, the increase of interstitial fibrosis in the adipose tissue could impair cell-cell contact and, therefore, interfere with cellular signaling mechanisms that regulate adipogenesis and metabolic functions of WAT.

    “Regardless of the actual mechanism explaining its persistence, the increase of interstitial fibrosis in the adipose tissue could impair cell-cell contact and, therefore, interfere with cellular signaling mechanisms that regulate adipogenesis and metabolic functions of WAT.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The resulting p values were adjusted for multiple testing errors by applying the Storey (2002) FDR correction approach.

    “The resulting p values were adjusted for multiple testing errors by applying the Storey (2002) FDR correction approach [68].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Storey JD, Tibshirani R: Statistical significance for genomewide studies. Proc Natl Acad Sci USA. 2003, 100: 9440-9445. 10.1073/pnas.1530509100. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    A print-tip loess normalization of the microarray experiments was performed after log-transformation of the background-corrected expression measurements.

    “A print-tip loess normalization of the microarray experiments was performed after the log-transformation of the background-corrected expression measurements, as indicated in [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Smyth GK, Speed T: Normalization of cDNA microarray data. Methods. 2003, 31: 265-273. 10.1016/S1046-2023(03)00155-5. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The threshold parameter, which represents a co-expression significance indicator, was determined by maximizing a scale-free topology criterion.

    “This threshold parameter, which represents a co-expression significance indicator, was determined by maximizing a scale-free topology criterion as previously described [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Zhang B, Horvath S: A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol. 2005, 4: Article 17-Epub 2005 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Significant differential expression was established by imposing a 5% FDR threshold in the SAM selection procedure for all conditions.

    “Significant differential expression was established by imposing a 5% FDR threshold in the SAM selection procedure for all conditions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Tusher VG, Tibshirani R, Chu G: Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA. 2001, 98: 5116-5121. 10.1073/pnas.091062498. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    SVF cells were used for cell culture at passage 2 to eliminate non-pre-adipocyte cell contamination, as confirmed by negative staining for macrophage markers (Ham 56 and Mac-1).

    “After washing in phosphate-buffered saline (PBS), the SVF cells were suspended in DMEM-10% fetal bovine serum and used for cell culture at passage 2 to eliminate non-pre-adipocyte cell contamination as confirmed by negative staining for macrophage markers (Ham 56 and Mac-1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    In all analyses the threshold for statistical significance was considered as corresponding to a p value < 0.05.

    “In all analyses the threshold for statistical significance was considered as corresponding to a p value < 0.05.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    18S ribosomal RNA was used as a normalization control.

    “We used 18S ribosomal RNA (Ribosomal RNA Control TaqMan Assay kit, Applied Biosystems, Foster City, CA, USA) as a normalization control.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    In all conditions in which multiple testing errors were expected, the p values were adjusted by applying the Storey (2002) correction approach, corresponding to an estimated FDR of 5%.

    “In all conditions in which multiple testing errors were expected, due to the high number of consecutive statistical computations, the p values computed from the aforementioned tests were adjusted by applying the Storey (2002) correction approach [68], corresponding to an estimated FDR of 5%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Storey JD, Tibshirani R: Statistical significance for genomewide studies. Proc Natl Acad Sci USA. 2003, 100: 9440-9445. 10.1073/pnas.1530509100. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Signed informed consents were obtained for all subjects involved in the study.

    “Signed informed consents were obtained for all subjects involved in the study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The enzymatic digestion technique used to separate adipocytes and SVF cells may have a potential influence on the expression profiles of the separated cells.

    “It cannot be excluded that this enzymatic digestion technique may have a potential influence on the expression profiles of separated cells, as noted previously in mouse studies [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Ruan H, Zarnowski MJ, Cushman SW, Lodish HF: Standard isolation of primary adipose cells from mouse epididymal fat pads induces inflammatory mediators and down-regulates adipocyte genes. J Biol Chem. 2003, 278: 47585-47593. 10.1074/jbc.M305257200. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    After expert inspection of automated annotation results, the fourth information-specific level of GO was retained for further analysis, as it provided an optimal trade-off between the specificity of the annotating information and its biological interpretability.

    “After expert inspection of automated annotation results, the fourth information-specific level of GO was retained for further analysis, as it provided an optimal trade-off between the specificity of the annotating information and its biological interpretability.”
    Quote in the paperNot a substantial claim
73 of 73

  • The paper relies on this without support.

    In chronic low-grade inflammatory diseases, prolonged inflammation stimuli result in tissue injuries that can lead to excessive synthesis of ECM elements and their progressive deposition.

    “In chronic low-grade inflammatory diseases, prolonged inflammation stimuli result in tissue injuries that can lead to excessive synthesis of ECM elements and their progressive deposition.”

  • The paper relies on this without support.

    ECM modulations are transmitted to integrin complexes that regulate cytoskeleton dynamics and intracellular pathways.

    “It is well known that ECM modulations are transmitted to integrin complexes that regulate cytoskeleton dynamics and intracellular pathways.”

  • The paper relies on this without support.

    Persistence of tissue injuries can lead over time to an excessive production of ECM components, which accumulate progressively and may result eventually in impaired tissular function.

    “The persistence of tissue injuries can lead over time to an excessive production of ECM components, which accumulate progressively and may result eventually in impaired tissular function.”

  • The paper relies on this without support.

    Once the obese phase is attained, the new weight status appears to be strongly defended by both biological and psychological regulatory mechanisms.

    “Once the obese phase is attained, the new weight status appears to be strongly defended by both biological and psychological regulatory mechanisms.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • One of 15 lean controls is reported as 6%

    Minor

    The table reports 1 of 15 lean controls as 6% in two risk-factor rows. That fraction is 6.67%, which rounds to 7% at the table's printed precision.

    Reported 6 · recomputed 6.666667

  • Figure 11 labels an electron-microscopy panel as a CD3-stained image

    Minor

    The caption identifies panel f as showing CD3-positive cells, but assigns panels e-g, including f, to electron microscopy rather than the immunohistochemistry shown in panels a-d.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Gene Expression Omnibus. [http://www.ncbi.nlm.nih.gov/geo/]

Cited by

Sorted by citations

Related

Authors
Henegar, C., Tordjman, J., Achard, V., Lacasa, D., Cremer, I., Guerre-Millo, M., Poitou, C., Basdevant, A., Stich, V., Viguerie, N., Langin, D., Bedossa, P., Zucker, J.-D., & Clement, K.
Affiliations
  • Inserm (FR)
  • Université Toulouse III - Paul Sabatier (FR)
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2008-01-21
Volume
9
Issue
1
Pages
R14-R14
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/gb-2008-9-1-r14
PMC
PMC2395253
OpenAlex
W2136425420
Semantic Scholar
a0031a71b94318afa099bb81af800d1555d245ae
Cited by
471
References
86
Citations by year
2026: 10 · 2025: 17 · 2024: 18 · 2023: 23 · 2022: 27 · 2021: 23 · 2020: 34 · 2019: 25 · 2018: 32 · 2017: 35 · 2016: 29 · 2015: 33 · 2014: 25 · 2013: 31 · 2012: 28
FWCI
19.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
Funders
  • Agence Nationale de la Recherche (ANR-05)
  • Institut National de la Santé et de la Recherche Médicale (4NU10G)
  • Assistance Publique - Hôpitaux de Paris
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
Keywords
obesity, white adipose tissue, extracellular matrix, gene expression signatures, low-grade inflammation, integrins, interstitial fibrosis, bariatric surgery, weight loss, preadipocytes, inflammatory cell infiltration, adipose tissue metabolism, gene co-expression network
MeSH terms
Adipose Tissue, Extracellular Matrix, Fibrosis, Humans, Inflammation, Obesity, Weight Loss, Gene Expression Profiling, Bariatric Surgery, Adipose Tissue, White

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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