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1.  Genetic Variation of PPARs 
PPAR Research  2009;2009:189091.
PMCID: PMC2792945  PMID: 20016799
2.  Methylation and Expression of Immune and Inflammatory Genes in the Offspring of Bariatric Bypass Surgery Patients 
Journal of Obesity  2013;2013:492170.
Background. Maternal obesity, excess weight gain and overnutrition during pregnancy increase risks of obesity, type 2 diabetes mellitus, and cardiovascular disease in the offspring. Maternal biliopancreatic diversion is an effective treatment for severe obesity and is beneficial for offspring born after maternal surgery (AMS). These offspring exhibit lower severe obesity prevalence and improved cardiometabolic risk factors including inflammatory marker compared to siblings born before maternal surgery (BMS). Objective. To assess relationships between maternal bariatric surgery and the methylation/expression of genes involved in the immune and inflammatory pathways. Methods. A differential gene methylation analysis was conducted in a sibling cohort of 25 BMS and 25 AMS offspring from 20 mothers. Following differential gene expression analysis (23 BMS and 23 AMS), pathway analysis was conducted. Correlations between gene methylation/expression and circulating inflammatory markers were computed. Results. Five immune and inflammatory pathways with significant overrepresentation of both differential gene methylation and expression were identified. In the IL-8 pathway, gene methylation correlated with both gene expression and plasma C-reactive protein levels. Conclusion. These results suggest that improvements in cardiometabolic risk markers in AMS compared to BMS offspring may be mediated through differential methylation of genes involved in immune and inflammatory pathways.
PMCID: PMC3693160  PMID: 23840945
3.  Influences of Gestational Obesity on Associations between Genotypes and Gene Expression Levels in Offspring following Maternal Gastrointestinal Bypass Surgery for Obesity 
PLoS ONE  2015;10(1):e0117011.
Maternal obesity and excess gestational weight gain with compromised metabolic fitness predispose offspring to lifelong obesity and its comorbidities. We demonstrated that compared to offspring born before maternal gastrointestinal bypass surgery (BMS) those born after (AMS) were less obese, with less cardiometabolic risk reflected in the expression and methylation of diabetes, immune and inflammatory pathway genes. Here we examine relationships between gestational obesity and offspring gene variations on expression levels.
Whole-genome genotyping and gene expression analyses in blood of 22 BMS and 23 AMS offspring from 19 mothers were conducted using Illumina HumanOmni-5-Quad and HumanHT-12 v4 Expression BeadChips, respectively. Using PLINK we analyzed interactions between offspring gene variations and maternal surgical status on offspring gene expression levels. Altered biological functions and pathways were identified and visualized using DAVID and Ingenuity Pathway Analysis.
Significant interactions (p ≤ 1.22x10-12) were found for 525 among the 16,060 expressed transcripts: 1.9% of tested SNPs were involved. Gene function and pathway analysis demonstrated enrichment of transcription and of cellular metabolism functions and overrepresentation of cellular stress and signaling, immune response, inflammation, growth, proliferation and development pathways.
We suggest that impaired maternal gestational metabolic fitness interacts with offspring gene variations modulating gene expression levels, providing potential mechanisms explaining improved cardiometabolic risk profiles of AMS offspring related to ameliorated maternal lipid and carbohydrate metabolism.
PMCID: PMC4300091  PMID: 25603303
4.  Effects of FADS and ELOVL polymorphisms on indexes of desaturase and elongase activities: results from a pre-post fish oil supplementation 
Genes & Nutrition  2014;9(6):437.
Polymorphisms (SNPs) within the FADS gene cluster and the ELOVL gene family are believed to influence enzyme activities after an omega-3 (n-3) fatty acid (FA) supplementation. The objectives of the study are to test whether an n-3 supplementation is associated with indexes of desaturase and elongase activities in addition to verify whether SNPs in the FADS gene cluster and the ELOVL gene family modulate enzyme activities of desaturases and elongases. A total 208 subjects completed a 6-week supplementation period with 5 g/day of fish oil (1.9–2.2 g/day of EPA + 1.1 g/day of DHA). FA profiles of plasma phospholipids were obtained by gas chromatography (n = 210). Desaturase and elongase indexes were estimated using product-to-precursor ratios. Twenty-eight SNPs from FADS1, FADS2, FADS3, ELOVL2 and ELOVL5 were genotyped using TaqMan technology. Desaturase indexes were significantly different after the 6-week n-3 supplementation. The index of δ-5 desaturase activity increased by 25.7 ± 28.8 % (p < 0.0001), whereas the index of δ-6 desaturase activity decreased by 17.7 ± 18.2 % (p < 0.0001) post-supplementation. Index of elongase activity decreased by 39.5 ± 27.9 % (p < 0.0001). Some gene–diet interactions potentially modulating the enzyme activities of desaturases and elongases involved in the FA metabolism post-supplementation were found. SNPs within the FADS gene cluster and the ELOVL gene family may play an important role in the enzyme activity of desaturases and elongases, suggesting that an n-3 FAs supplementation may affect PUFA metabolism.
PMCID: PMC4235832  PMID: 25367143
Omega-3 fatty acids; Diet and dietary lipids; Genomics; Fish oil; Omega-6 fatty acids; Genotype
5.  Differences in Transcriptional Activation by the Two Allelic (L162V Polymorphic) Variants of PPARα after Omega-3 Fatty Acids Treatment 
PPAR Research  2009;2009:369602.
Omega-3 fatty acids (FAs) have the potential to regulate gene expression via the peroxisome proliferator-activated receptor α (PPARα); therefore, genetic variations in this gene may impact its transcriptional activity on target genes. It is hypothesized that the transcriptional activity by wild-type L162-PPARα is enhanced to a greater extent than the mutated variant (V162-PPARα) in the presence of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or a mixture of EPA:DHA. To examine the functional difference of the two allelic variants on receptor activity, transient co-transfections were performed in human hepatoma HepG2 cells activated with EPA, DHA and EPA:DHA mixtures. Results indicate that the addition of EPA or DHA demonstrate potential to increase the transcriptional activity by PPARα with respect to basal level in both variants. Yet, the EPA:DHA mixtures enhanced the transcriptional activity to a greater extent than individual FAs indicating possible additive effects of EPA and DHA. Additionally, the V162 allelic form of PPARα demonstrated consistently lower transcriptional activation when incubated with EPA, DHA or EPA:DHA mixtures than, the wild-type variant. In conclusion, both allelic variants of the PPARα L162V are activated by omega-3 FAs; however, the V162 allelic form displays a lower transcriptional activity than the wild-type variant.
PMCID: PMC2649533  PMID: 19266045
6.  SREBF1 gene variations modulate insulin sensitivity in response to a fish oil supplementation 
An important inter-individual variability in the response of insulin sensitivity following a fish oil supplementation has been observed. The objective was to examine the associations between single nucleotide polymorphisms (SNPs) within sterol regulatory element binding transcription factor 1 (SREBF1) gene and the response of insulin sensitivity to a fish oil supplementation.
Participants (n = 210) were recruited in the greater Quebec City area and followed a 6-week fish oil supplementation protocol (5 g/day: 1.9-2.2 g EPA; 1.1 g DHA). Insulin sensitivity was assessed by the quantitative insulin sensitivity check index (QUICKI). Three tag SNPs (tSNPs) within SREBF1 gene were genotyped according to TAQMAN methodology.
Three tSNPs (rs12953299, rs4925118 and rs4925115) covered 100% of the known genetic variability within SREBF1 gene. None of the three tSNPs was associated with either baseline fasting insulin concentrations (rs12953299, rs4925118 and rs4925115) (p = 0.29, p = 0.20 and p = 0.70, respectively) or QUICKI (p = 0.20, p = 0.18 and p = 0.76, respectively). The three tSNPs (rs12953299, rs4925118 and rs4925115) were associated with differences in the response of plasma insulin levels (p = 0.01, p = 0.005 and p = 0.004, respectively) and rs12953299 as well as rs4925115 were associated with the insulin sensitivity response (p = 0.009 and p = 0.01, respectively) to the fish oil supplementation, independently of the effects of age, sex and BMI.
The genetic variability within SREBF1 gene has an impact on the insulin sensitivity in response to a fish oil supplementation.
Trial registration NCT01343342.
PMCID: PMC4196000  PMID: 25270430
SREBF1 gene; Fish oil supplementation; Insulin sensitivity; Inter-individual variability; Polymorphisms
7.  Gene-diet interactions with polymorphisms of the MGLL gene on plasma low-density lipoprotein cholesterol and size following an omega-3 polyunsaturated fatty acid supplementation: a clinical trial 
Omega-3 (n-3) polyunsaturated fatty acid (PUFA) consumption increases low-density lipoprotein (LDL) cholesterol (C) concentrations and particle size. Studies showed that individuals with large, buoyant LDL particles have decreased risk of cardiovascular diseases. However, a large inter-individual variability is observed in LDL particle size. Genetic factors may explain the variability of LDL-C concentrations and particle size after an n-3 PUFA supplementation. The monoglyceride lipase (MGLL) enzyme, encoded by the MGLL gene, plays an important role in lipid metabolism, especially lipoprotein metabolism. The aim of this study was to investigate if polymorphisms (SNPs) of the MGLL gene influence the variability of LDL-C and LDL particle size in response to an n-3 PUFA supplementation.
210 subjects completed the study. They consumed 5 g/d of a fish oil supplement (1.9-2.2 g eicosapentaenoic acid and 1.1 g docosaexaenoic acid) during 6 weeks. Plasma lipids were measured before and after the supplementation period and 18 SNPs of the MGLL gene, covering 100% of common genetic variations (minor allele frequency ≥0.05), have been genotyped using TaqMan technology (Life Technologies Inc., Burlington, ON, CA).
Following the n-3 PUFA supplementation, 55% of subjects increased their LDL-C levels. In a model including the supplementation, genotype and supplementation*genotype effects, gene-diet interaction effects on LDL-C concentrations (rs782440, rs6776142, rs555183, rs6780384, rs6787155 and rs1466571) and LDL particle size (rs9877819 and rs13076593) were observed for the MGLL gene SNPs (p < 0.05).
SNPs within the MGLL gene may modulate plasma LDL-C levels and particle size following an n-3 PUFA supplementation. This trial was registered at as NCT01343342.
PMCID: PMC4040477  PMID: 24884512
Omega-3 polyunsaturated fatty acids; Nutrigenomics; MGLL; LDL cholesterol; LDL particle size
8.  An interaction effect between glucokinase gene variation and carbohydrate intakes modulates the plasma triglyceride response to a fish oil supplementation 
Genes & Nutrition  2014;9(3):395.
A large inter-individual variability in the plasma triglyceride (TG) response to fish oil consumption has been observed. The objective was to investigate the gene–diet interaction effects between single-nucleotide polymorphisms (SNPs) within glucokinase (GCK) gene and dietary carbohydrate intakes (CHO) on the plasma TG response to a fish oil supplementation. Two hundred and eight participants were recruited in the greater Quebec City area. The participants completed a 6-week fish oil supplementation (5 g fish oil/day: 1.9–2.2 g EPA and 1.1 g DHA). Thirteen SNPs within GCK gene were genotyped using TAQMAN methodology. A gene–diet interaction effect on the plasma TG response was observed with rs741038 and CHO adjusted for age, sex and BMI (p = 0.008). In order to compare the plasma TG response between genotypes according to CHO, participants were divided according to median CHO. Homozygotes of the minor C allele of rs741038 with high CHO >48.59 % had a greater decrease in their plasma TG concentrations following the intake of fish oil (p < 0.05) than C/C homozygotes with low CHO and also than the other genotypes either with high or low CHO. The plasma TG response to a fish oil supplementation may be modulated by gene–diet interaction effects involving GCK gene and CHO.
Electronic supplementary material
The online version of this article (doi:10.1007/s12263-014-0395-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4026435  PMID: 24643341
Glucokinase; Carbohydrate; Fish oil; Triglyceride; Gene–diet interaction
9.  Polymorphisms in Genes Involved in Fatty Acid β-Oxidation Interact with Dietary Fat Intakes to Modulate the Plasma TG Response to a Fish Oil Supplementation 
Nutrients  2014;6(3):1145-1163.
A large inter-individual variability in the plasma triglyceride (TG) response to an omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation has been observed. The objective was to examine gene-diet interaction effects on the plasma TG response after a fish oil supplementation, between single-nucleotide polymorphisms (SNPs) within genes involved in fatty acid β-oxidation and dietary fat intakes. Two hundred and eight (208) participants were recruited in the greater Quebec City area. The participants completed a six-week fish oil supplementation (5 g fish oil/day: 1.9–2.2 g EPA and 1.1 g DHA). Dietary fat intakes were measured using three-day food records. SNPs within RXRA, CPT1A, ACADVL, ACAA2, ABCD2, ACOX1 and ACAA1 genes were genotyped using TAQMAN methodology. Gene-diet interaction effects on the plasma TG response were observed for SNPs within RXRA (rs11185660, rs10881576 and rs12339187) and ACOX1 (rs17583163) genes. For rs11185660, fold changes in RXRA gene expression levels were different depending on SFA intakes for homozygotes T/T. Gene-diet interaction effects of SNPs within genes involved in fatty acid β-oxidation and dietary fat intakes may be important in understanding the inter-individual variability in plasma TG levels and in the plasma TG response to a fish oil supplementation.
PMCID: PMC3967183  PMID: 24647074
gene-diet interaction; omega-3 polyunsaturated fatty acid; fish oil; fatty acid β-oxidation; single nucleotide polymorphism; triglyceride
10.  The metabolic signature associated with the Western dietary pattern: a cross-sectional study 
Nutrition Journal  2013;12:158.
Metabolic profiles have been shown to be associated to obesity status and insulin sensitivity. Dietary intakes influence metabolic pathways and therefore, different dietary patterns may relate to modifications in metabolic signatures. The objective was to verify associations between dietary patterns and metabolic profiles composed of amino acids (AAs) and acylcarnitines (ACs).
210 participants were recruited in the greater Quebec City area between September 2009 and December 2011. Dietary patterns had been previously derived using principal component analysis (PCA). The Prudent dietary pattern was characterised by higher intakes of vegetables, fruits, whole grain products, non-hydrogenated fat and lower intakes of refined grain products, whereas the Western dietary pattern was associated with higher intakes of refined grain products, desserts, sweets and processed meats. Targeted metabolites were quantified in 37 participants with the Biocrates Absolute IDQ p150 (Biocrates Life Sciences AG, Austria) mass spectrometry method (including 14 amino acids and 41 acylcarnitines).
PCA analysis with metabolites including AAs and ACs revealed two main components explaining the most variance in overall data (13.8%). PC1 was composed mostly of medium- to long-chain ACs (C16:2, C14:2, C14:2-OH, C16, C14:1-OH, C14:1, C10:2, C5-DC/C6-OH, C12, C18:2, C10, C4:1-DC/C6, C8:1 and C2) whereas PC2 included certain AAs and short-chain ACs (xLeu, Met, Arg, Phe, Pro, Orn, His, C0, C3, C4 and C5). The Western dietary pattern correlated negatively with PC1 and positively with PC2 (r = −0.34, p = 0.05 and r = 0.38, p = 0.03, respectively), independently of age, sex and BMI.
These findings suggest that the Western dietary pattern is associated with a specific metabolite signature characterized by increased levels of AAs including branched-chain AAs (BCAAs) and short-chain ACs.
Trial registration
PMCID: PMC3874609  PMID: 24330454
Dietary pattern; Western dietary pattern; Prudent dietary pattern; Acylcarnitine; Amino acids; Branched-chain amino acids; Metabolites
11.  Polymorphisms in Fatty Acid Desaturase (FADS) Gene Cluster: Effects on Glycemic Controls Following an Omega-3 Polyunsaturated Fatty Acids (PUFA) Supplementation 
Genes  2013;4(3):485-498.
Changes in desaturase activity are associated with insulin sensitivity and may be associated with type 2 diabetes mellitus (T2DM). Polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene cluster have been associated with the homeostasis model assessment of insulin sensitivity (HOMA-IS) and serum fatty acid composition. Objective: To investigate whether common genetic variations in the FADS gene cluster influence fasting glucose (FG) and fasting insulin (FI) responses following a 6-week n-3 polyunsaturated fatty acids (PUFA) supplementation. Methods: 210 subjects completed a 2-week run-in period followed by a 6-week supplementation with 5 g/d of fish oil (providing 1.9 g–2.2 g of EPA + 1.1 g of DHA). Genotyping of 18 SNPs of the FADS gene cluster covering 90% of all common genetic variations (minor allele frequency ≥ 0.03) was performed. Results: Carriers of the minor allele for rs482548 (FADS2) had increased plasma FG levels after the n-3 PUFA supplementation in a model adjusted for FG levels at baseline, age, sex, and BMI. A significant genotype*supplementation interaction effect on FG levels was observed for rs482548 (p = 0.008). For FI levels, a genotype effect was observed with one SNP (rs174456). For HOMA-IS, several genotype*supplementation interaction effects were observed for rs7394871, rs174602, rs174570, rs7482316 and rs482548 (p = 0.03, p = 0.01, p = 0.03, p = 0.05 and p = 0.07; respectively). Conclusion: Results suggest that SNPs in the FADS gene cluster may modulate plasma FG, FI and HOMA-IS levels in response to n-3 PUFA supplementation.
PMCID: PMC3924828  PMID: 24705214
metabolic pathways; genotype; FADS gene cluster; polyunsaturated fatty acid omega-3; insulin insensitivity; glucose metabolism; homeostasis model assessment
12.  Differences in metabolomic and transcriptomic profiles between responders and non-responders to an n-3 polyunsaturated fatty acids (PUFAs) supplementation 
Genes & Nutrition  2012;8(4):411-423.
Studies have demonstrated large within-population heterogeneity in plasma triacylglycerol (TG) response to n-3 PUFA supplementation. The objective of the study was to compare metabolomic and transcriptomic profiles of responders and non-responders of an n-3 PUFA supplementation. Thirty subjects completed a 2-week run-in period followed by a 6-week supplementation with n-3 PUFA (3 g/d). Six subjects did not lower their plasma TG (+9 %) levels (non-responders) and were matched to 6 subjects who lowered TG (−41 %) concentrations (responders) after the n-3 PUFA supplementation. Pre-n-3 PUFA supplementation characteristics did not differ between the non-responders and responders except for plasma glucose concentrations. In responders, changes were observed for plasma hexose concentrations, docosahexaenoic acid, stearoyl-CoA-desaturase-18 ratio, and the extent of saturation of glycerophosphatidylcholine after n-3 PUFA supplementation; however, no change in these parameters was observed in non-responders. Transcriptomic profiles after n-3 PUFA supplementation indicate changes in glycerophospholipid metabolism in both subgroups and sphingolipid metabolism in non-responders. Six key genes in lipid metabolism: fatty acid desaturase 2, phospholipase A2 group IVA, arachidonate 15-lipoxygenase, phosphatidylethanolamine N-methyltransferase, monoglyceride lipase, and glycerol-3-phosphate acyltransferase, were expressed in opposing direction between subgroups. In sum, results highlight key differences in lipid metabolism of non-responders compared to responders after an n-3 PUFA supplementation, which may explain the inter-individual variability in plasma TG response.
Electronic supplementary material
The online version of this article (doi:10.1007/s12263-012-0328-0) contains supplementary material, which is available to authorized users.
PMCID: PMC3689890  PMID: 23250786
Lipidomics; Metabolic pathways; Metabolites; Microarray; Nutrigenomics
13.  Associations between dietary patterns and gene expression profiles of healthy men and women: a cross-sectional study 
Nutrition Journal  2013;12:24.
Diet regulates gene expression profiles by several mechanisms. The objective of this study was to examine gene expression in relation with dietary patterns.
Two hundred and fifty four participants from the greater Quebec City metropolitan area were recruited. Two hundred and ten participants completed the study protocol. Dietary patterns were derived from a food frequency questionnaire (FFQ) by factor analysis. For 30 participants (in fasting state), RNA was extracted from peripheral blood mononuclear cells (PBMCs) and expression levels of 47,231 mRNA transcripts were assessed using the Illumina Human-6 v3 Expression BeadChips®. Microarray data was pre-processed with Flexarray software and analysed with Ingenuity Pathway Analysis (IPA).
Two dietary patterns were identified. The Prudent dietary pattern was characterised by high intakes of vegetables, fruits, whole grain products and low intakes of refined grain products and the Western dietary pattern, by high intakes of refined grain products, desserts, sweets and processed meats. When individuals with high scores for the Prudent dietary pattern where compared to individuals with low scores, 2,083 transcripts were differentially expressed in men, 1,136 transcripts in women and 59 transcripts were overlapping in men and women. For the Western dietary pattern, 1,021 transcripts were differentially expressed in men with high versus low scores, 1,163 transcripts in women and 23 transcripts were overlapping in men and women. IPA reveals that genes differentially expressed for both patterns were present in networks related to the immune and/or inflammatory response, cancer and cardiovascular diseases.
Gene expression profiles were different according to dietary patterns, which probably modulate the risk of chronic diseases.
Trial Registration
NCT: NCT01343342
PMCID: PMC3598224  PMID: 23398686
Dietary patterns; Western dietary pattern; Prudent dietary pattern; Gene expression; Transcriptomics
14.  Comparison of the dipeptidyl peptidase-4 gene methylation levels between severely obese subjects with and without the metabolic syndrome 
The dipeptidyl peptidase-4 (DPP4) enzyme is a novel adipokine potentially involved in the development of the metabolic syndrome (MetS). Previous observations demonstrated higher visceral adipose tissue (VAT) DPP4 gene expression in non-diabetic severely obese men with (MetS+) vs. without (MetS−) MetS. DPP4 mRNA abundance in VAT correlated also with CpG site methylation levels (%Meth) localized within and near its exon 2 (CpG94 to CpG102) in non-diabetic severely obese women, regardless of their MetS status. The actual study tested whether DPP4 %Meth levels in VAT are different between MetS− and MetS+ non-diabetic severely obese subjects, whether variable metabolic and plasma lipid profiles are observed between DPP4 %Meth quartiles, and whether correlation exists in DPP4 %Meth levels between VAT and white blood cells (WBCs).
DNA was extracted from the VAT of 26 men (MetS−: n=12, MetS+: n=14) and 79 women (MetS−: n=60; MetS+: n=19), as well as from WBCs in a sub-sample of 17 women (MetS−: n=9; MetS+: n=8). The %Meth levels of CpG94 to CpG102 were assessed by pyrosequencing of sodium bisulfite-treated DNA. ANOVA analyses were used to compare the %Meth of CpGs between MetS− and MetS+ groups, and to compare the metabolic phenotype and plasma lipid levels between methylation quartiles. Pearson correlation coefficient analyses were computed to test the relationship between VAT and WBCs CpG94-102 %Meth levels.
No difference was observed in CpG94-102 %Meth levels between MetS− and MetS+ subjects in VAT (P=0.67), but individuals categorized into CpG94-102 %Meth quartiles had variable plasma total-cholesterol concentrations (P=0.04). The %Meth levels of four CpGs in VAT were significantly correlated with those observed in WBCs (r=0.55−0.59, P≤0.03).
This study demonstrated that %Meth of CpGs localized within and near the exon 2 of the DPP4 gene in VAT are not associated with MetS status. The actual study also revealed an association between the %Meth of this locus with plasma total-cholesterol in severe obesity, which suggests a link between the DPP4 gene and plasma lipid levels.
PMCID: PMC3637825  PMID: 23379505
DNA methylation; Epigenetics; DPP4 gene; Visceral adipose tissue; White blood cells; Plasma cholesterol
15.  Transcriptomic profiles of skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in insulin-resistant obese subjects 
Genes & Nutrition  2012;8(1):91-98.
Insulin resistance in skeletal muscle is an early phenomenon in the pathogenesis of type 2 diabetes. Muscle is mainly responsible for insulin-stimulated glucose clearance from the bloodstream. Thus, regulation of gene expression in muscle tissue may be involved in the pathogenesis of insulin resistance. The objective was to investigate gene expression and metabolic pathways alterations in skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in obese insulin-resistant subjects. We carried out a transcriptome comparison of skeletal muscle tissue before and after a 3-h euglycemic-hyperinsulinemic clamp following 8-week supplementation with n-3 polyunsaturated fatty acid (PUFA) (1.8 g/day) with or without a supplement of fish gelatin (FG) (25 % of daily protein intake) in 16 obese insulin-resistant subjects. Results indicate that approximately 5 % (1932) of expressed transcripts were significantly changed after the clamp in both n-3 PUFA and n-3 PUFA + FG supplementation periods. Of these differentially expressed transcripts, 1394 genes associated with enzymes, transcription and translation regulators, transporters, G protein-coupled receptors, cytokines, and ligand-dependent nuclear receptors were modified. Metabolic pathways that were significantly modified included liver X receptor/retinoid X receptors (RXR) activation, vitamin D receptor/RXR activation, interleukin (IL)-8, acute phase response, IL10, triggering receptor expressed on myeloid cells 1, peroxisome proliferator-activated receptor, G-beta/gamma and hepatocyte growth factor and IL6 signaling. Taken together, results suggest that mainly inflammatory and transcription factors are modified following clamp in obese insulin-resistant subjects. Overall, understanding the changes in metabolic pathways due to insulin may be a potential target for the management of insulin resistance.
PMCID: PMC3534998  PMID: 22566203
Diabetes; Obesity; Microarray; Gene expression; Metabolic pathways
16.  Association between Polymorphisms in the Fatty Acid Desaturase Gene Cluster and the Plasma Triacylglycerol Response to an n-3 PUFA Supplementation 
Nutrients  2012;4(8):1026-1041.
Eicosapentaenoic and docosahexaenoic acids have been reported to have a variety of beneficial effects on cardiovascular disease risk factors. However, a large inter-individual variability in the plasma lipid response to an omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation is observed in different studies. Genetic variations may influence plasma lipid responsiveness. The aim of the present study was to examine the effects of a supplementation with n-3 PUFA on the plasma lipid profile in relation to the presence of single-nucleotide polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene cluster. A total of 208 subjects from Quebec City area were supplemented with 3 g/day of n-3 PUFA, during six weeks. In a statistical model including the effect of the genotype, the supplementation and the genotype by supplementation interaction, SNP rs174546 was significantly associated (p = 0.02) with plasma triglyceride (TG) levels, pre- and post-supplementation. The n-3 supplementation had an independent effect on plasma TG levels and no significant genotype by supplementation interaction effects were observed. In summary, our data support the notion that the FADS gene cluster is a major determinant of plasma TG levels. SNP rs174546 may be an important SNP associated with plasma TG levels and FADS1 gene expression independently of a nutritional intervention with n-3 PUFA.
PMCID: PMC3448085  PMID: 23016130
triacylglycerol; metabolic pathways; lipids; genotypes; FADS gene cluster; polyunsaturated fatty acid omega-3
17.  Omega-3 fatty acids status in human subjects estimated using a food frequency questionnaire and plasma phospholipids levels 
Nutrition Journal  2012;11:46.
Intakes of omega-3 (n-3) fatty acids (FA) are associated with several health benefits. The aim of this study was to verify whether intakes of n-3 FA estimated from a food frequency questionnaire (FFQ) correlate with n-3 FA levels measured in plasma phospholipids (PL).
The study sample consisted of 200 French-Canadians men and women aged between 18 to 55 years. Dietary data were collected using a validated FFQ. Fasting blood samples were collected and the plasma PL FA profile was measured by gas chromatography.
Low intakes of n-3 long-chain FA together with low percentages of n-3 long-chain FA in plasma PL were found in French-Canadian population. Daily intakes of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) were similar between men and women. Yet, alpha-linolenic acid (ALA) and total n-3 FA intakes were significantly higher in men compared to women (ALA: 2.28 g and 1.69 g, p < 0.0001, total n-3 FA: 2.57 g and 1.99 g, p < 0.0001; respectively). In plasma PL, DPA and DHA percentages were significantly different between men and women (DPA: 1.03% and 0.88%, p < 0.0001, DHA: 3.00% and 3.43%, p = 0.0005; respectively). Moreover, DHA (men: r = 0.52, p < 0.0001; women: r = 0.57, p < 0.0001) and total n-3 FA (men: r = 0.47, p < 0.0001; women: r = 0.52, p < 0.0001) intakes were positively correlated to their respective plasma PL FA levels. In women, EPA (r = 0.44, p < 0.0001) and DPA (r = 0.23, p = 0.02) intakes were also correlated respectively with EPA and DPA plasma PL FA percentages.
Estimated n-3 long-chain FA intake among this young and well-educated French-Canadian population is lower than the recommendations. Further, FFQ data is comparable to plasma PL results to estimate DHA and total n-3 FA status in healthy individuals as well as to evaluate the EPA and DPA status in women. Overall, this FFQ could be used as a simple, low-cost tool in future studies to rank n-3 FA status of individuals.
PMCID: PMC3412753  PMID: 22775977
Food frequency questionnaire; Plasma phospholipids; n-3 PUFA; Biomarker; Gas chromatography
18.  LINE-1 methylation in visceral adipose tissue of severely obese individuals is associated with metabolic syndrome status and related phenotypes 
Clinical Epigenetics  2012;4(1):10.
Epigenetic mechanisms may be involved in the regulation of genes found to be differentially expressed in the visceral adipose tissue (VAT) of severely obese subjects with (MetS+) versus without (MetS-) metabolic syndrome (MetS). Long interspersed nuclear element 1 (LINE-1) elements DNA methylation levels (%meth) in blood, a marker of global DNA methylation, have recently been associated with fasting glucose, blood lipids, heart diseases and stroke.
To test whether LINE-1%meth levels in VAT are associated with MetS phenotypes and whether they can predict MetS risk in severely obese individuals.
DNA was extracted from VAT of 34 men (MetS-: n = 14, MetS+: n = 20) and 152 premenopausal women (MetS-: n = 84; MetS+: n = 68) undergoing biliopancreatic diversion for the treatment of obesity. LINE-1%meth levels were assessed by pyrosequencing of sodium bisulfite-treated DNA.
The mean LINE-1%meth in VAT was of 75.8% (SD = 3.0%). Multiple linear regression analyses revealed that LINE-1%meth was negatively associated with fasting glucose levels (β = -0.04; P = 0.03), diastolic blood pressure (β =  -0.65; P = 0.03) and MetS status (β = -0.04; P = 0.004) after adjustments for the effects of age, sex, waist circumference (except for MetS status) and smoking. While dividing subjects into quartiles based on their LINE-1%meth (Q1 to Q4: lower %meth to higher %meth levels), greater risk were observed in the first (Q1: odds ratio (OR) = 4.37, P = 0.004) and the second (Q2: OR = 4.76, P = 0.002) quartiles compared to Q4 (1.00) when adjusting for age, sex and smoking.
These results suggest that lower global DNA methylation, assessed by LINE-1 repetitive elements methylation analysis, would be associated with a greater risk for MetS in the presence of obesity.
PMCID: PMC3464682  PMID: 22748066
Blood pressure; Epigenetics; Fasting glucose; Global DNA methylation; LINE-1; Metabolic syndrome; Severe obesity; Visceral adipose tissue
19.  The effect of mere-measurement of cognitions on physical activity behavior: a randomized controlled trial among overweight and obese individuals 
The promotion of physical activity among an overweight/obese population is an important challenge for clinical practitioners and researchers. In this regard, completing a questionnaire on cognitions could be a simple and easy strategy to increase levels of physical activity. Thus, the aim of the present study was to test the effect of completing a questionnaire based on the Theory of Planned Behavior (TPB) on the level of physical activity.
Overall, 452 overweight/obese adults were recruited and randomized to the experimental or control group. At baseline, participants completed a questionnaire on cognitions regarding their participation in leisure-time physical activity (experimental condition) versus a questionnaire on fruit and vegetable consumption (control condition). The questionnaires assessed the TPB variables that are beliefs, attitude, norm, perception of control, intention and a few additional variables from other theories. At three-month follow-up, leisure-time physical activity was self-reported by means of a short questionnaire. An analysis of covariance with baseline physical activity level as covariate was used to verify the effect of the intervention.
At follow-up, 373 participants completed the leisure-time physical activity questionnaire. The statistical analysis showed that physical activity participation was greater among participants in the experimental condition than those in the control condition (F(1,370) = 6.85, p = .009, d = 0.20).
Findings indicate that completing a TPB questionnaire has a significant positive impact on subsequent participation in physical activity. Consequently, asking individuals to complete such a questionnaire is a simple, inexpensive and easy strategy to increase the level of physical activity among overweight/obese adults.
PMCID: PMC3023726  PMID: 21223565
20.  Omega-3 fatty acids regulate gene expression levels differently in subjects carrying the PPARα L162V polymorphism 
Genes & Nutrition  2009;4(3):199-205.
Omega-3 fatty acids (FAs) are natural ligands of the peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor that modulates expression levels of genes involved in lipid metabolism. The L162V polymorphism of the PPARα gene is associated with a deteriorated metabolic profile. We postulate that subjects carrying the PPARα-V162 allele exhibit differences in the expression of PPARα and its target genes after incubation with omega-3 FAs compared with L162 homozygotes. Peripheral blood monocytes from six men carrying the PPARα-V162 allele paired for age and for body mass index with six L162 homozygotes were differentiated into macrophages and activated with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or mixtures of EPA:DHA. Data demonstrates that gene expression levels of PPARα and apolipoprotein AI (APOA1) were significantly lower for carriers of the PPARα-V162 allele compared to L162 homozygotes after the addition of DHA and a mixture of EPA:DHA. Additionally, lipoprotein lipase (LPL) gene expression displayed a tendency to be lower in the PPARα L162V polymorphism subgroup after the addition of a mixture of EPA:DHA. Consequently, individuals carrying the PPARα-V162 allele may demonstrate inferior improvements in their lipid profile due to alterations in gene expression rates in response to omega-3 FA supplementation.
PMCID: PMC2745745  PMID: 19585164
Eicosapentaenoic acid; Docosahexaenoic acid; PPARα; Lipoprotein lipase; Apolipoprotein AI; Triglycerides
21.  Validity of a self-reported measure of familial history of obesity 
Nutrition Journal  2008;7:27.
Familial history information could be useful in clinical practice. However, little is known about the accuracy of self-reported familial history, particularly self-reported familial history of obesity (FHO).
Two cross-sectional studies were conducted. The aims of study 1 was to compare self-reported and objectively measured weight and height whereas the aims of study 2 were to examine the relationship between the weight and height estimations reported by the study participants and the values provided by their family members as well as the validity of a self-reported measure of FHO. Study 1 was conducted between 2004 and 2006 among 617 subjects and study 2 was conducted in 2006 among 78 participants.
In both studies, weight and height reported by the participants were significantly correlated with their measured values (study 1: r = 0.98 and 0.98; study 2: r = 0.99 and 0.97 respectively; p < 0.0001). Estimates of weight and height for family members provided by the study participants were strongly correlated with values reported by each family member (r = 0.96 and 0.95, respectively; p < 0.0001). Substantial agreement between the FHO reported by the participants and the one obtained by calculating the BMI of each family members was observed (kappa = 0.72; p < 0.0001). Sensitivity (90.5%), specificity (82.6%), positive (82.6%) and negative (90.5%) predictive values of FHO were very good.
A self-reported measure of FHO is valid, suggesting that individuals are able to detect the presence or the absence of obesity in their first-degree family members.
PMCID: PMC2543037  PMID: 18783616
22.  Moderators of the intention-behaviour and perceived behavioural control-behaviour relationships for leisure-time physical activity 
Intention is a key determinant of action. However, there is a gap between intention and behavioural performance that remains to be explained. Therefore, the aim of this study was to identify moderators of the intention-behaviour and perceived behavioural control (PBC)- behaviour relationships for leisure-time physical activity.
This was tested in reference to Ajzen's Theory of Planned Behaviour. A sample of 300 volunteers, 192 women and 108 men, aged 18 to 55, participated in the study. At baseline, the participants completed a self-administrated psychosocial questionnaire assessing Ajzen's theory variables (i.e., intention and perceived behavioural control). The behavioural measure was obtained by mail three months later.
Multiple hierarchical regression analyses indicated that age and annual income moderated the intention-behaviour and PBC-behaviour relationships. However, in the final model predicting behaviour (R2 = .46), only the interaction term of PBC by annual income (β = .24, p = 0.0003) significantly contributed to the prediction of behaviour along with intention (β = .49, p = 0.0009) and past behaviour (β = .44, p < 0.0001).
Physical activity promotion programs would benefit not only from focusing on increasing the intention of low intenders, but also from targeting factors that moderate the perceived behavioural control-behaviour relationships.
PMCID: PMC2275296  PMID: 18241339
23.  Dietary patterns and associated lifestyles in individuals with and without familial history of obesity: a cross-sectional study 
Familial history of obesity (FHO) and certain dietary habits are risk factors for obesity. The objectives of this cross-sectional study were 1) to derive dietary patterns using factor analysis in a population of men and women with and without FHO; 2) to compare mean factor scores for each dietary pattern between individuals with and without FHO; and 3) to examine the association between these patterns and anthropometric, lifestyle and sociodemographic variables.
A total of 197 women and 129 men with a body mass index <30 kg/m2 were recruited. A positive FHO (FHO+) was defined as having at least one obese first-degree relative and a negative FHO (FHO-) as no obese first-degree relative. Dietary data were collected from a food frequency questionnaire. Factor analysis was performed to derive dietary patterns. Mean factor scores were compared using general linear model among men and women according to FHO. Regression analyses were performed to study the relationship between anthropometric, lifestyle and sociodemographic variables, and each dietary pattern.
Two dietary patterns were identified in both men and women : the Western pattern characterized by a higher consumption of red meats, poultry, processed meats, refined grains as well as desserts, and the Prudent pattern characterized by greater intakes of vegetables, fruits, non-hydrogenated fat, and fish and seafood. Similar Western and Prudent factor scores were observed in individual with and without FHO. In men with FHO+, the Western pattern is negatively associated with age and positively associated with physical activity, smoking, and personal income. In women with FHO-, the Prudent pattern is negatively associated with BMI and smoking and these pattern is positively associated with age and physical activity.
Two dietary patterns have been identified among men and women with and without FHO. Although that FHO does not seem to influence the adherence to dietary patterns, results of this study suggest that anthropometric, lifestyle and sociodemographic variables associated with dietary patterns differ according to FHO and gender.
PMCID: PMC1635721  PMID: 17076904
24.  PPARα: A Master Regulator of Bilirubin Homeostasis 
PPAR Research  2014;2014:747014.
Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR) α to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARα agonists, namely, fenofibrate, gemfibrozil, and Wy14,643, affect bilirubin synthesis and metabolism. Human umbilical vein epithelial cells (HUVEC) and coronary artery smooth muscle cells (CASMC) were cultured in the absence or presence of the 3 activators, and mRNA, protein, and/or activity levels of the bilirubin synthesizing heme oxygenase- (HO-) 1 and biliverdin reductase (BVR) enzymes were determined. Human hepatocytes (HH) and HepG2 cells sustained similar treatments, except that the expression of the bilirubin conjugating UDP-glucuronosyltransferase (UGT) 1A1 enzyme and multidrug resistance-associated protein (MRP) 2 transporter was analyzed. In HUVECs, gemfibrozil, fenofibrate, and Wy14,643 upregulated HO-1 mRNA expression without affecting BVR. Wy14,643 and fenofibrate also caused HO-1 protein accumulation, while gemfibrozil and fenofibrate favored the secretion of bilirubin in cell media. Similar positive regulations were also observed with the 3 PPARα ligands in CASMCs where HO-1 mRNA and protein levels were increased. In HH and HepG2 cells, both UGT1A1 and MRP2 transcripts were also accumulating. These observations indicate that PPARα ligands activate bilirubin synthesis in vascular cells and metabolism in liver cells. The clinical implications of these regulatory events are discussed.
PMCID: PMC4134828  PMID: 25147562
25.  A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance 
Manning, Alisa K. | Hivert, Marie-France | Scott, Robert A. | Grimsby, Jonna L. | Bouatia-Naji, Nabila | Chen, Han | Rybin, Denis | Liu, Ching-Ti | Bielak, Lawrence F. | Prokopenko, Inga | Amin, Najaf | Barnes, Daniel | Cadby, Gemma | Hottenga, Jouke-Jan | Ingelsson, Erik | Jackson, Anne U. | Johnson, Toby | Kanoni, Stavroula | Ladenvall, Claes | Lagou, Vasiliki | Lahti, Jari | Lecoeur, Cecile | Liu, Yongmei | Martinez-Larrad, Maria Teresa | Montasser, May E. | Navarro, Pau | Perry, John R. B. | Rasmussen-Torvik, Laura J. | Salo, Perttu | Sattar, Naveed | Shungin, Dmitry | Strawbridge, Rona J. | Tanaka, Toshiko | van Duijn, Cornelia M. | An, Ping | de Andrade, Mariza | Andrews, Jeanette S. | Aspelund, Thor | Atalay, Mustafa | Aulchenko, Yurii | Balkau, Beverley | Bandinelli, Stefania | Beckmann, Jacques S. | Beilby, John P. | Bellis, Claire | Bergman, Richard N. | Blangero, John | Boban, Mladen | Boehnke, Michael | Boerwinkle, Eric | Bonnycastle, Lori L. | Boomsma, Dorret I. | Borecki, Ingrid B. | Böttcher, Yvonne | Bouchard, Claude | Brunner, Eric | Budimir, Danijela | Campbell, Harry | Carlson, Olga | Chines, Peter S. | Clarke, Robert | Collins, Francis S. | Corbatón-Anchuelo, Arturo | Couper, David | de Faire, Ulf | Dedoussis, George V | Deloukas, Panos | Dimitriou, Maria | Egan, Josephine M | Eiriksdottir, Gudny | Erdos, Michael R. | Eriksson, Johan G. | Eury, Elodie | Ferrucci, Luigi | Ford, Ian | Forouhi, Nita G. | Fox, Caroline S | Franzosi, Maria Grazia | Franks, Paul W | Frayling, Timothy M | Froguel, Philippe | Galan, Pilar | de Geus, Eco | Gigante, Bruna | Glazer, Nicole L. | Goel, Anuj | Groop, Leif | Gudnason, Vilmundur | Hallmans, Göran | Hamsten, Anders | Hansson, Ola | Harris, Tamara B. | Hayward, Caroline | Heath, Simon | Hercberg, Serge | Hicks, Andrew A. | Hingorani, Aroon | Hofman, Albert | Hui, Jennie | Hung, Joseph | Jarvelin, Marjo Riitta | Jhun, Min A. | Johnson, Paul C.D. | Jukema, J Wouter | Jula, Antti | Kao, W.H. | Kaprio, Jaakko | Kardia, Sharon L. R. | Keinanen-Kiukaanniemi, Sirkka | Kivimaki, Mika | Kolcic, Ivana | Kovacs, Peter | Kumari, Meena | Kuusisto, Johanna | Kyvik, Kirsten Ohm | Laakso, Markku | Lakka, Timo | Lannfelt, Lars | Lathrop, G Mark | Launer, Lenore J. | Leander, Karin | Li, Guo | Lind, Lars | Lindstrom, Jaana | Lobbens, Stéphane | Loos, Ruth J. F. | Luan, Jian’an | Lyssenko, Valeriya | Mägi, Reedik | Magnusson, Patrik K. E. | Marmot, Michael | Meneton, Pierre | Mohlke, Karen L. | Mooser, Vincent | Morken, Mario A. | Miljkovic, Iva | Narisu, Narisu | O’Connell, Jeff | Ong, Ken K. | Oostra, Ben A. | Palmer, Lyle J. | Palotie, Aarno | Pankow, James S. | Peden, John F. | Pedersen, Nancy L. | Pehlic, Marina | Peltonen, Leena | Penninx, Brenda | Pericic, Marijana | Perola, Markus | Perusse, Louis | Peyser, Patricia A | Polasek, Ozren | Pramstaller, Peter P. | Province, Michael A. | Räikkönen, Katri | Rauramaa, Rainer | Rehnberg, Emil | Rice, Ken | Rotter, Jerome I. | Rudan, Igor | Ruokonen, Aimo | Saaristo, Timo | Sabater-Lleal, Maria | Salomaa, Veikko | Savage, David B. | Saxena, Richa | Schwarz, Peter | Seedorf, Udo | Sennblad, Bengt | Serrano-Rios, Manuel | Shuldiner, Alan R. | Sijbrands, Eric J.G. | Siscovick, David S. | Smit, Johannes H. | Small, Kerrin S. | Smith, Nicholas L. | Smith, Albert Vernon | Stančáková, Alena | Stirrups, Kathleen | Stumvoll, Michael | Sun, Yan V. | Swift, Amy J. | Tönjes, Anke | Tuomilehto, Jaakko | Trompet, Stella | Uitterlinden, Andre G. | Uusitupa, Matti | Vikström, Max | Vitart, Veronique | Vohl, Marie-Claude | Voight, Benjamin F. | Vollenweider, Peter | Waeber, Gerard | Waterworth, Dawn M | Watkins, Hugh | Wheeler, Eleanor | Widen, Elisabeth | Wild, Sarah H. | Willems, Sara M. | Willemsen, Gonneke | Wilson, James F. | Witteman, Jacqueline C.M. | Wright, Alan F. | Yaghootkar, Hanieh | Zelenika, Diana | Zemunik, Tatijana | Zgaga, Lina | Wareham, Nicholas J. | McCarthy, Mark I. | Barroso, Ines | Watanabe, Richard M. | Florez, Jose C. | Dupuis, Josée | Meigs, James B. | Langenberg, Claudia
Nature genetics  2012;44(6):659-669.
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction, but contributed little to our understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways may be uncovered by accounting for differences in body mass index (BMI) and potential interaction between BMI and genetic variants. We applied a novel joint meta-analytical approach to test associations with fasting insulin (FI) and glucose (FG) on a genome-wide scale. We present six previously unknown FI loci at P<5×10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496non-diabetic individuals. Risk variants were associated with higher triglyceride and lower HDL cholesterol levels, suggestive of a role for these FI loci in insulin resistance pathways. The localization of these additional loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
PMCID: PMC3613127  PMID: 22581228

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