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Tchernof, André

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Tchernof

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André

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CHU de Québec-Université Laval

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  • PublicationAccès libre
    Molecular remodeling of adipose tissue is associated with metabolic recovery after weight loss surgery
    (Springer Nature, 2022-06-23) Toro Martin, Juan de; Biertho, Laurent; Lebel, Stéfane; Bouchard-Mercier, Annie; Lescelleur, Odette; Nadeau, Mélanie; Richard, Denis; Vohl, Marie-Claude; Tchernof, André
    Background Bariatric surgery is an effective therapy for individuals with severe obesity to achieve sustainable weight loss and to reduce comorbidities. Examining the molecular signature of subcutaneous adipose tissue (SAT) following different types of bariatric surgery may help in gaining further insight into their distinct metabolic impact. Results Subjects undergoing biliopancreatic diversion with duodenal switch (BPD-DS) showed a significantly higher percentage of total weight loss than those undergoing gastric bypass or sleeve gastrectomy (RYGB + SG) (41.7 ± 4.6 vs 28.2 ± 6.8%; p = 0.00005). Individuals losing more weight were also significantly more prone to achieve both type 2 diabetes and dyslipidemia remission (OR = 0.75; 95%CI = 0.51–0.91; p = 0.03). Whole transcriptome and methylome profiling showed that bariatric surgery induced a profound molecular remodeling of SAT at 12 months postoperative, mainly through gene down-regulation and hypermethylation. The extent of changes observed was greater following BPD-DS, with 61.1% and 49.8% of up- and down-regulated genes, as well as 85.7% and 70.4% of hyper- and hypomethylated genes being exclusive to this procedure, and mostly associated with a marked decrease of immune and inflammatory responses. Weight loss was strongly associated with genes being simultaneously differentially expressed and methylated in BPD-DS, with the strongest association being observed for GPD1L (r²=0.83; p=1.4x10⁻⁶). Conclusions Present findings point to the greater SAT molecular remodeling following BPD-DS as potentially linked with higher metabolic remission rates. These results will contribute to a better understanding of the metabolic pathways involved in the response to bariatric surgery and will eventually lead to the development of gene targets for the treatment of obesity.
  • PublicationAccès libre
    Temporal changes in gene expression profile during mature adipocyte dedifferentiation
    (Hindawi Publishing Corporation, 2017-03-19) Guénard, Frédéric; Biron, Simon; Lapointe, Marc-André; Vohl, Marie-Claude; Côté, Julie Anne; Lessard, Julie.; Tchernof, André
    Objective. To characterize changes in gene expression profile during human mature adipocyte dedifferentiation in ceiling culture. Methods. Subcutaneous (SC) and omental (OM) adipose tissue samples were obtained from 4 participants paired for age and BMI. Isolated adipocytes were dedifferentiated in ceiling culture. Gene expression analysis at days 0, 4, 7, and 12 of the cultures was performed using Affymetrix Human Gene 2.0 STvi arrays. Hierarchical clustering according to similarity of expression changes was used to identify overrepresented functions. Results. Four clusters gathered genes with similar expression between day 4 to day 7 but decreasing expression from day 7 to day 12. Most of these genes coded for proteins involved in adipocyte functions (LIPE, PLIN1, DGAT2, PNPLA2, ADIPOQ, CEBPA, LPL, FABP4, SCD, INSR, and LEP). Expression of several genes coding for proteins implicated in cellular proliferation and growth or cell cycle increased significantly from day 7 to day 12 (WNT5A, KITLG, and FGF5). Genes coding for extracellular matrix proteins were differentially expressed between days 0, 4, 7, and 12 (COL1A1, COL1A2, and COL6A3, MMP1, and TGFB1). Conclusion. Dedifferentiation is associated with downregulation of transcripts encoding proteins involved in mature adipocyte functions and upregulation of genes involved in matrix remodeling, cellular development, and cell cycle.
  • PublicationAccès libre
    Methylation quantitative trait loci within the TOMM20 gene are associated with metabolic syndrome-related lipid alterations in severely obese subjects
    (BioMed Central Ltd., 2016-07-29) Toro Martin, Juan de; Guénard, Frédéric; Pérusse, Louis; Hould, Frédéric-Simon; Marceau, Picard; Vohl, Marie-Claude; Deshaies, Yves; Lebel, Stéfane; Tchernof, André
    Background : The TOMM20 gene was previously identified as differentially expressed and methylated between severely obese subjects with and without metabolic syndrome (MS). Since metabolic complications do not affect all obese patients to the same extent, the aim of this study was to identify methylation quantitative trait loci (meQTL) potentially associated with MS-related complications within the TOMM20 locus. Methods : Methylation profiling, SNP genotyping and meQTL association tests (general linear models) were performed in a population of 48 severely obese subjects. Genotyping was extended to a larger population of 1720 severely obese subjects with or without MS, where genotype- and diplotype-based association tests were assessed by logistic regression. In silico analyses were performed using TRAP. Results : Four SNPs were identified as significant meQTLs for the differentially methylated site cg16490124. Individuals carrying rare alleles of rs4567344 (A > G) (P = 4.9 × 10−2) and rs11301 (T > C) (P = 5.9 × 10−3) showed decreased methylation levels at this site, whereas those carrying rare alleles of rs4551650 (T > C) (P = 3.5 × 10−15) and rs17523127 (C > G) (P = 3.5 × 10−15) exhibited a significant increase in methylation. rs4567344 and rs11301 were associated with increased susceptibility to exhibit high plasma triglycerides (TG ≥ 1.69 mmol/L), while rare alleles of rs4551650 and rs17523127 were significantly more represented in the low plasma total-C group (total-C ≤ 6.2 mmol/L). Haplotype reconstruction with the four meQTLs (rs4567344, rs11301, rs4551650, rs17523127) led to the identification of ten different diplotypes, with H1/H2 (GCGG/ACGG) exhibiting a nearly absence of methylation at cg16490124, and showing the highest risk of elevated plasma TG levels [OR = 2.03 (1.59–3.59)], a novel association with elevated LDL-cholesterol [OR = 1.86 (1.06–3.27)] and the complete inversion of the protective effect on total-C levels [OR = 2.03 (1.59–3.59)], especially in men. In silico analyses revealed that rs17523127 overlapped the CpG site cg16490124 and encompassed the core binding sites of the transcription factors Egr 1, 2 and 3, located within the TOMM20 promoter region. Conclusion : This study demonstrates that TOMM20 SNPs associated with MS-related lipid alterations are meQTLs potentially exerting their action through a CpG methylation-dependent effect. The strength of the diplotype-based associations may denote a novel meQTL additive action and point to this locus as particularly relevant in the inter-individual variability observed in the metabolic profiles of obese subjects.
  • PublicationRestreint
    Single-cell analysis of human adipose tissue identifies depot and disease specific cell types
    (Nature Research, 2019-12-23) Vijay, Jinchu; Biertho, Laurent; Gauthier, Marie-Frédérique; Vohl, Marie-Claude; Biswell, Rebecca L.; Tchernof, André; Louiselle, Daniel A.; Johnston, Jeffrey J.; Cheung, Warren A.; Belden, Bradley; Pramatarova, Albena; Gibson, Margaret E.; Simon, Marie-Michelle; Djambazian, Haïg; Staffa, Alfredo; Bourque, Guillaume; Laitinen, Anita; Nystedt, Johanna; Fraser, Jason D.; Pastinen, Tomi; Grundberg, Elin
    The complex relationship between metabolic disease risk and body fat distribution in humans involves cellular characteristics that are specific to body fat compartments. Here we show depot-specific differences in the stromal vascular fraction of visceral and subcutaneous adipose tissue by performing single-cell RNA sequencing of tissue specimens from obese individuals. We characterize multiple immune cells, endothelial cells, fibroblasts, adipose and haematopoietic stem cell progenitors. Subpopulations of adipose-resident immune cells are metabolically active and associated with metabolic disease status, including a population of potential dysfunctional CD8+ T cells that express metallothioneins. We identify multiple types of adipocyte progenitors that are common across depots, including a subtype enriched in individuals with type 2 diabetes. Depot-specific analysis reveals a class of adipocyte progenitors unique to visceral adipose tissue, which shares common features with beige pre-adipocytes. Our human single-cell transcriptome atlas across fat depots provides a resource to dissect the functional genomics of metabolic disease.
  • PublicationAccès libre
    Relevance of omental pericellular adipose tissue collagen in the pathophysiology of human abdominal obesity and related cardiometabolic risk
    (Newman [for] the Association for the Study of Obesity, 2016-10-04) Laforest, Sofia; Tordjman, Joan; Pelletier, Mélissa; Michaud, Andréanne; Liu, Yuejun; Tchernof, André; Noël, Suzanne; Le Naour, Gilles; Bouchard, Céline; Clément, Karine
    Background: Adipose tissue fibrosis is a relatively new notion and its relationship with visceral obesity and cardiometabolic alterations remains unclear, particularly in moderate obesity. Objective: Our objective was to examine if total and pericellular collagen accumulation are relevant for the pathophysiology of visceral obesity and related cardiometabolic risk. Subjects and methods: Surgical omental (OM) and subcutaneous (SC) fat samples were obtained in 56 women (age: 47.2±5.8 years; body mass index (BMI): 27.1±4.4 kg/m2). Body composition and fat distribution were measured by dual-energy X-ray absorptiometry and computed tomography, respectively. Total and pericellular collagen were measured using picrosirius red staining. CD68+ cells (total macrophages) and CD163+ cells (M2-macrophages) were identified using immunohistochemistry. Results: We found that only pericellular collagen percentage, especially in OM fat, was associated with higher BMI, body fat mass and adipose tissue areas as well as lower radiologic attenuation of visceral adipose tissue and altered cardiometabolic risk variables. Strong correlations between peri-adipocyte collagen percentage and total or M2-macrophage percentages were observed in both depots. Total collagen percentage in either compartment was not related to adiposity, fat distribution or cardiometabolic risk. Conclusions: As opposed to whole tissue-based assessments of adipose tissue fibrosis, collagen deposition around the adipocyte, especially in the OM fat compartment is related to total and regional adiposity as well as altered cardiometabolic risk profile.
  • PublicationAccès libre
    Expression and activity of aldoketoreductases 1C in omental adipose tissue are positive correlates of adiposity in women
    (American Physiological Society, 2005-02-01) Blouin, Karine; Blanchette, Sophie; Dupont, Pierre; Richard, Christian; Luu-The, Van; Tchernof, André
    We examined the expression and activity of steroid aldoketoreductase (AKR) 1C enzymes in abdominal subcutaneous and omental adipose tissue in women. AKR1C1 (20-hydroxysteroid dehydrogenase), AKR1C2 (3-hydroxysteroid dehydrogenase type 3), and AKR1C3 (17-hydroxysteroid dehydrogenase type 5) are involved mainly in the conversion of progesterone to 20-hydroxyprogesterone and in the inactivation of dihydrotestosterone to 5-androstane3,17-diol. Abdominal subcutaneous (Sc) and omental (Om) adipose tissue biopsies were obtained during abdominal hysterectomies in 7 women with low visceral adipose tissue area and 7 age- and total body fat mass-matched women with visceral obesity. Body composition and body fat distribution were assessed before surgery by dual energy x-ray absorptiometry and computed tomography. Women with elevated visceral adipose tissue areas were characterized by significantly higher Om adipose tissue 20-HSD and 3-HSD-3 mRNA abundance compared to women with low visceral adipose tissue accumulations (1.4 and 1.6 fold differences respectively, p<0.05). Om and Sc adipose tissue 3-HSD activities were significantly higher in women with high vs. low visceral adipose tissue areas (p<0.05 for both comparisons). Total and visceral adiposity measures were positively associated with Om 20-HSD mRNA level (r=0.75, p<0.003 for fat mass and r=0.57, p<0.04 for visceral adipose tissue area) and Om 3-HSD-3 mRNA level (r=0.68, p<0.01 for fat mass and r=0.74, p<0.003 for visceral adipose tissue area). Enzyme activities in both the Sc and Om depots were also positively and significantly correlated with total and abdominal adiposity measures, respectively. Omental adipose tissue enzyme expression and activity were positively associated with omental adipocyte size and LPL activity. In conclusion, mRNA abundance and activity of AKR1C enzymes in abdominal adipose tissue compartments are positive correlates of adiposity measures in women. Further studies are required to elucidate whether increased inactivation of progesterone and/or dihydrotestosterone in abdominal adipose tissue impacts locally on fat metabolism in abdominally obese women.
  • PublicationAccès libre
    Histomorphometric analyses of human adipose tissues using intact, flash-frozen samples
    (Springer-Verlag, 2018-01-22) Laforest, Sofia; Pelletier, Mélissa; Michaud, Andréanne; Daris, Marleen; Tchernof, André; Descamps, Justine; Soulet, Denis; Jensen, Michael D.
    Histomorphometric analyses of adipose tissue usually require formalin fixation of fresh samples. Our objective was to determine if intact, flash-frozen whole adipose tissue samples stored at − 80 °C could be used for measurements developed for fresh-fixed adipose tissues. Portions of adipose tissue samples were either formalin-fixed immediately upon sampling or flash-frozen and stored at − 80 °C and then formalin-fixed during the thawing process. Mean adipocyte diameter was measured. Immunohistochemistry was performed on additional samples to identify macrophage subtypes (M1, CD14 + and M2, CD206 +) and total (CD68 +) number. All slides were counterstained using haematoxylin and eosin (H&E). Visual inspection of H&E-stained adipose tissue slides performed in a blinded fashion showed little or no sign of cell breakage in 74% of frozen-fixed samples and in 68% of fresh-fixed samples (p > 0.5). There was no difference in the distribution frequencies of adipocyte sizes in fresh-fixed vs. frozen-fixed tissues in both depots (p > 0.9). Mean adipocyte size from frozen-fixed samples correlated significantly and positively with adipocyte size from fresh-fixed samples (r = 0.74, p < 0.0001, for both depots). The quality of staining/immunostaining and appearance of tissue architecture were comparable in fresh-fixed vs. frozen-fixed samples. In conclusion, intact flash-frozen adipose tissue samples stored at − 80 °C can be used to perform techniques conventionally applied to fresh-fixed samples. This approach allows for retrospective studies with frozen human adipose tissue samples.
  • PublicationRestreint
    Polygenic risk score for predicting weight loss after bariatric surgery
    (American Society for Clinical Investigation, 2018-09-06) Guénard, Frédéric; Toro Martin, Juan de; Pérusse, Louis; Marceau, Simon; Vohl, Marie-Claude; Tchernof, André
    BACKGROUND. The extent of weight loss among patients undergoing bariatric surgery is highly variable. Herein, we tested the contribution of genetic background to such interindividual variability after biliopancreatic diversion with duodenal switch. METHODS. Percentage of excess body weight loss (%EBWL) was monitored in 865 patients over a period of 48 months after bariatric surgery, and 2 polygenic risk scores were constructed with 186 and 11 (PRS₁₈₆ and PRS₁₁) single nucleotide polymorphisms previously associated with BMI. RESULTS. The accuracy of the %EBWL logistic prediction model — including initial BMI, age, sex, and surgery modality, and assessed as the area under the receiver operating characteristics (ROC) curve adjusted for optimism ((AUCadj= 0.867) — significantly increased after the inclusion of PRS186 (ΔAUCadj = 0.021; 95% CI of the difference (95% CIdiff) = 0.0046–0.038) but not PRS11 (ΔAUCadj= 0.008; 95% CIdiff= –0.003–0.019). The overall fit of the longitudinal linear mixed model for %EBWL showed a significant increase after addition of PRS₁₈₆ (–2 log-likelihood = 12.3; P = 0.002) and PRS11 (–2 log-likelihood = 9.9; P = 0.007). A significant interaction with postsurgery time was found for PRS₁₈₆ (β = –0.003; P = 0.008) and PRS₁₁ (β = –0.008; P = 0.03). The inclusion of PRS₁₈₆ and PRS₁₁ into the model improved the cost-effectiveness of bariatric surgery by reducing the percentage of false negatives from 20.4% to 10.9% and 10.2%, respectively. CONCLUSION. These results revealed that genetic background has a significant impact on weight loss after biliopancreatic diversion with duodenal switch. Likewise, the improvement in weight loss prediction after addition of polygenic risk scores is cost-effective, suggesting that genetic testing could potentially be used in the presurgical assessment of patients with severe obesity.
  • PublicationRestreint
    Transcriptomic and metabolomic signatures of an n-3 polyunsaturated fatty acids 2 supplementation in a normolipidemic/normocholesterolemic Caucasian population
    (Elsevier, 2012-06-28) Thifault, Elisabeth; Paradis, Ann-Marie; Rudkowska, Iwona; Barbier, Olivier; Lemieux, Simone; Julien, Pierre; Vohl, Marie-Claude; Couture, Patrick; Tchernof, André
    OMIC technologies, including transcriptomics and metabolomics, may provide powerful tools for identifying the effects of nutrients on molecular functions and metabolic pathways. The objective was to investigate molecular and metabolic changes following n-3 polyunsaturated fatty acid (PUFA) supplementation in healthy subjects via traditional biomarkers as well as transcriptome and metabolome analyses. Thirteen men and 17 women followed a 2-week run-in period based on Canada's Food Guide and then underwent 6-week supplementation with n-3 PUFA (3 g/day). Traditional biochemical markers such as plasma lipids, inflammatory markers, glycemic parameters and erythrocyte fatty acid concentrations were measured. Changes in gene expression of peripheral blood mononuclear cells were assessed by microarrays, and metabolome profiles were assessed by mass spectrometry assay kit. After supplementation, plasma triglycerides decreased and erythrocyte n-3 PUFA concentrations increased to a similar extent in both genders. Further, plasma high-density lipoprotein cholesterol concentrations and fasting glucose levels increased in women after n-3 PUFA supplementation. N-3 PUFA supplementation changed the expression of 610 genes in men, whereas the expression of 250 genes was altered in women. Pathway analyses indicate changes in gene expression of the nuclear receptor peroxisome proliferator-activated receptor-alpha, nuclear transcription-factor kappaB, oxidative stress and activation of the oxidative stress response mediated by nuclear factor (erythroid-derived 2)-like 2. After n-3 PUFA supplementation, metabolomics profiles demonstrate an increase in acylcarnitines, hexose and leucine in men only and a decrease in saturation of glycerophosphatidylcholine and lysophosphatidylcholine concentrations in all subjects. Overall, traditional and novel biomarkers suggest that n-3 PUFA supplementation exerts cardioprotective effects.
  • PublicationAccès libre
    Use of blood as a surrogate model for the assessment of visceral adipose tissue methylation profiles associated with the metabolic syndrome in men
    (Library Pub. Media, 2016-01-12) Guénard, Frédéric; Hould, Frédéric-Simon; Deshaies, Yves; Marceau, Picard; Vohl, Marie-Claude; Lebel, Stéfane; Tchernof, André
    Epigenetic mechanisms are known to be involved in tissue-specific differentiation. DNA methylation patterns have been shown to be largely conserved across tissues but with variation for specific genes. However, it is unclear whether the variability observed in the methylation profile of a metabolically active tissue is reflected in other sources such as hematopoietic tissue. This study aimed to test blood genome-wide CpG site methylation levels as a surrogate model for visceral adipose tissue (VAT) methylation and to verify whether it appropriately reflects differences in methylation levels found in VAT between men discordant for the metabolic syndrome (MetS). Tissue specimens (VAT and blood samples) were obtained from 16 severely obese individuals discordant for the MetS. CpG sites methylation levels were measured with the Infinium HumanMethylation450 BeadChip and correlations of methylation levels between VAT and blood were computed. Differences in methylation levels between individuals with and without MetS were tested in both tissues. Pathway analysis was conducted for differentially methylated CpG sites common to both tissues. High cross-tissue correlations were observed for VAT and blood (0.952±0.014) while some CpG sites had significantly different methylation levels in VAT versus blood. Differential methylation analysis between individuals with and without MetS demonstrated a higher number of differentially methylated CpG sites in VAT than in blood (11,778 vs. 881, respectively) with nearly 4% of differentially methylated sites found in VAT being also represented in blood. Common differentially methylated sites were involved in inflammatory-, lipid- and diabetes-related pathways. These results suggest that blood methylation levels of specific CpG sites may adequately reflect VAT methylation levels for some of the MetS-related genes, specifically for inflammatory, lipid and glucose metabolism genes.