Peroxisome proliferator‐activated receptor γ (PPARγ) and its response gene, Acyl CoA synthetase 5 (ACSL5), which has an important role in fatty acid metabolism, may affect weight loss in response to caloric restriction. Therefore, we... more
Peroxisome proliferator‐activated receptor γ (PPARγ) and its response gene, Acyl CoA synthetase 5 (ACSL5), which has an important role in fatty acid metabolism, may affect weight loss in response to caloric restriction. Therefore, we aimed to determine whether these genes were involved in the interindividual response to dietary treatment. Genotypic/phenotypic comparisons were made between selected obese women from the quintiles losing the most (diet responsive, n = 74) and the quintiles losing the least (diet‐resistant, n = 67) weight in the first 6 weeks of a 900‐kcal formula diet. Two common PPARγ single nucleotide polymorphisms, Pro12Ala and C1431T, and eight polymorphisms across the ACSL5 gene were selected for single locus and haplotypic association analyses. The PPARγ Pro12Ala single nucleotide polymorphism was associated with diet resistance (odds ratio = 3.48, 95% confidence interval = 1.41 to 8.56, p = 0.03), and the rs2419621, located in the 5′untranslated region of the ACSL5 gene, displayed the strongest association with diet response (odds ratio = 3.45, 95% confidence interval = 1.61 to 7.69, p = 0.001). Skeletal muscle ACSL5 mRNA expression was significantly lower in carriers of the wildtype compared with the variant rs2419621 allele (p = 0.03). Our results suggest a link between PPARγ2 and ACSL5 genotype and diet responsiveness.
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a Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada b Ruddy Canadian Cardiovascular Genetics Centre, Ottawa, Ontario, Canada c Atherogenomics Laboratory, and... more
a Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada b Ruddy Canadian Cardiovascular Genetics Centre, Ottawa, Ontario, Canada c Atherogenomics Laboratory, and Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada d Ottawa Hospital Weight Management Clinic, Ottawa, Ontario, Canada
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Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity... more
Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity to switch between fatty acid and glucose substrates) are altered in obesity, with some changes proceeding and some following the development of the disease. Nonetheless, there are marked interindividual differences in skeletal muscle composition and metabolism in obesity, some of which have been associated with obesity risk and weight loss capacity. In this review, we discuss related molecular mechanisms and how current and novel treatment strategies may enhance weight loss capacity, particularly in diet-resistant obesity.
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Understanding the function of a locus is a challenge in molecular biology. Although numerous molecular data have been generated in the last decades, it remains difficult to grasp, how these data are related at a locus? In this study, we... more
Understanding the function of a locus is a challenge in molecular biology. Although numerous molecular data have been generated in the last decades, it remains difficult to grasp, how these data are related at a locus? In this study, we describe an analytical workflow that can solve this problem using the knowledge available at single-nucleotide polymorphisms (SNPs) level. The underlying algorithm uses SNPs as connectors to link omics data and identify correlation between them through a joint bioinformatical/statistical approach. We describe its application in finding the mechanism whereby a mutation causes a phenotype and in revealing the path whereby a gene is being regulated and impacts the phenotypes. We translated our workflow into freely available shell scripts that carry out the analyses. Our approach provides a basic framework to solve the information overload problem in biology.
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Canadian Surgery Forum1 Is laparoscopic sleeve gastrectomy a reasonable stand-alone procedure for super morbidly obese patients?2 Postoperative monitoring requirements of patients with obstructive sleep apnea undergoing bariatric surgery3 Role of relaparoscopy in the diagnosis and treatment of ba...more
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Abstract For weight loss to occur, thermogenesis, or energy expenditure, must exceed dietary energy intake. Coupled thermogenesis refers to the energy expended to produce cellular adenosine triphosphate, which is used in turn to support... more
Abstract For weight loss to occur, thermogenesis, or energy expenditure, must exceed dietary energy intake. Coupled thermogenesis refers to the energy expended to produce cellular adenosine triphosphate, which is used in turn to support cellular work. During ...
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The physiological function of uncoupling protein 3 (UCP3) is as yet unknown. Based on its 57% homology to UCP1 whose physiologic function is uncoupling and thermogenesis, UCP3 was attributed with the function of mitochondrial uncoupling... more
The physiological function of uncoupling protein 3 (UCP3) is as yet unknown. Based on its 57% homology to UCP1 whose physiologic function is uncoupling and thermogenesis, UCP3 was attributed with the function of mitochondrial uncoupling through proton-leak reactions. UCP3 is expressed selectively in muscle, a tissue in which it has been estimated that proton leak accounts for approx. 50% of resting energy metabolism. Genetic linkage, association and variant studies suggest a role for UCP3 in obesity and/or diabetes. Studies of the heterologous expression of UCP3 in yeast provide support for the idea that UCP3 can uncouple mitochondrial oxidative phosphorylation, but the physiological relevance of these results is questionable. In vitro studies of mitochondria from Ucp3− − mice provide support, but there are no changes in resting metabolic rate (RMR) of mice. In vivo studies demonstrate increased ATP synthesis, but estimates of substrate oxidation rate indicate no change. Mice that g...
Research Interests: Biology, Mitochondria, Medicine, Ion Channels, Mice, and 13 moreAnimals, Muscles, Ucp, Molecular cloning, Basal metabolic rate (BMR), Oxidative phosphorylation, Thermogenesis, Uncoupling Protein, Protons, Biochemistry and cell biology, Mitochondrion, Mitochondrial Proteins, and Medical biochemistry and metabolomics
The effects of β-blockers on metabolic parameters including weight loss are poorly understood. From a database of 3582 patients who completed The Ottawa Hospital Weight Management Program between 1992 and 2011, a total of 173 patients... more
The effects of β-blockers on metabolic parameters including weight loss are poorly understood. From a database of 3582 patients who completed The Ottawa Hospital Weight Management Program between 1992 and 2011, a total of 173 patients were receiving β-blockers and were eligible for the study. We determined differences in rate of weight loss in the first 6 weeks of this 900 kcal/d Optifast (Nestlé Health Science, Vevey, Switzerland) meal replacement program for patients treated with β-blockers compared with (1) matched controls and (2) all participants in the program not being treated with β-blockers. Secondary outcomes included changes in waist circumference. Mean percent weight loss in the β-blocker group was reduced compared with the rest of the group (9.7% vs 10.0%; P = 0.0001) as well as with matched controls (9.7% vs 10.3%; P = 0.004). Results were the same after adjusting for prevalent cardiovascular disease (9.7% vs 10.0%; P = 0.006). Similarly, a smaller decrease in waist circumference at 6 weeks was observed in the β-blocker-treated group compared with the rest of the group (-24.2 vs -26.3 cm; P = 0.002) and with matched controls (-24.2 vs -25.2 cm; P = 0.04) and was not altered by adjustment for cardiovascular disease (-24.2 vs 26.3 cm; P = 0.004). In the absence of a clear medical indication, alternatives to β-blockers should be considered for the treatment of hypertension in obese individuals.
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Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to... more
Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3, whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11. Finally, we noted that ra...
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Weight loss in response to energy restriction is highly variable, and identification of genetic contributors can provide insights into underlying biology. Leveraging 1000 Genomes imputed genotypes, we carried out genome-wide association... more
Weight loss in response to energy restriction is highly variable, and identification of genetic contributors can provide insights into underlying biology. Leveraging 1000 Genomes imputed genotypes, we carried out genome-wide association study (GWAS) analysis in 551 unrelated obese subjects of European ancestry who participated in an intensively supervised weight loss program with replication of promising signals in an independent sample of 1,331 obese subjects who completed the program at a later date. By single nucleotide polymorphism–based and sib-pair analysis, we show that that weight loss is a heritable trait, with estimated heritability (h2 = 0.49) within the range reported for obesity. We find rs679482, intronic to SGCG (sarcoglycan γ), highly expressed in skeletal muscle, to concordantly associate with weight loss in discovery and replication samples reaching GWAS significance in the combined meta-analysis (β = −0.35, P = 1.7 × 10−12). Located in a region of open chromatin, ...
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Aims To identify genetic variants that have a regulatory impact on circulating microRNAs (miRNAs) and to connect genetic risk to blood traits/biomarkers through the circulating miRNAs. Methods and results Leveraging miRNA-Seq data and the... more
Aims To identify genetic variants that have a regulatory impact on circulating microRNAs (miRNAs) and to connect genetic risk to blood traits/biomarkers through the circulating miRNAs. Methods and results Leveraging miRNA-Seq data and the 1000 Genomes imputed genotypes, we carried out genome-wide association analysis for SNPs that regulate the expression of circulating miRNAs in a sample of 710 unrelated subjects of European ancestry. Wherever possible, we used data from the Framingham and the Geuvadis studies to replicate our findings. We found at least one genome-wide significant (P
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Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden,... more
Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which > 80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synt...
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Recent genome-wide association studies have identified multiple loci robustly associated with plasma lipids, which also contribute to extreme lipid phenotypes. However, these common genetic variants explain <12% of variation in lipid... more
Recent genome-wide association studies have identified multiple loci robustly associated with plasma lipids, which also contribute to extreme lipid phenotypes. However, these common genetic variants explain <12% of variation in lipid traits. Adiposity is also an important determinant of plasma lipoproteins, particularly plasma TGs and HDL cholesterol (HDLc) concentrations. Thus, interactions between genes and clinical phenotypes may contribute to this unexplained heritability. We have applied a weighted genetic risk score (GRS) for both plasma TGs and HDLc in two large cohorts at the extremes of BMI. Both BMI and GRS were strongly associated with these lipid traits. A significant interaction between obese/lean status and GRS was noted for each of TG (P(Interaction) = 2.87 × 10(-4)) and HDLc (P(Interaction) = 1.05 × 10(-3)). These interactions were largely driven by SNPs tagging APOA5, glucokinase receptor (GCKR), and LPL for TG, and cholesteryl ester transfer protein (CETP), GalN...
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Growing epidemics of obesity and asthma are major public health concerns. Despite that asthma-obesity links are widely studied, the effects of weight loss on asthma severity measured by airway hyper-responsiveness (AHR) have received... more
Growing epidemics of obesity and asthma are major public health concerns. Despite that asthma-obesity links are widely studied, the effects of weight loss on asthma severity measured by airway hyper-responsiveness (AHR) have received limited attention. Our main study objective was to examine whether weight reduction reduces asthma severity in adult obese-asthmatics. In a prospective controlled parallel group study, we followed 22 obese-asthmatic subjects aged 18-75 years, with a body mass index (BMI) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;32.5kg/m2 and airway hyper-responsiveness (PC20&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;16mg/mL of methacholine). Sixteen subjects followed a behavioural weight reduction program for 3 months and 6 subjects were controls. The primary outcome was change in AHR over 3 months. Changes in lung function, asthma control and quality of life were secondary outcomes. At study entry, subjects&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; mean age was 44 years (SD±9), 95% were females with mean BMI of 45.7kg/m2 (SD±9.2). After 3 months, mean weight loss was 16.5kg (SD± 9.9) in the weight loss group but controls had a mean weight gain of 0.6kg (SD±2.6). There were significant improvements in PC20 to methacholine (p=0.009), FEV1 (p=0.009), FVC (p=0.010), asthma-control (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) and asthma quality of life (p=0.003) in the intervention group whilst these parameters remained unchanged in the control group. Physical activity levels also increased significantly in the intervention group but not in the controls. Weight loss in obese-asthmatics can improve asthma severity and result in improvements in AHR, asthma control, lung function, and quality of life. These findings support the need to actively pursue healthy weight loss measures in obese-asthmatics.
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Weight loss success in response to energy restriction is highly variable. This may be due in part to differences in mitochondrial function and oxidative stress. The objective of the study was to determine whether mitochondrial function,... more
Weight loss success in response to energy restriction is highly variable. This may be due in part to differences in mitochondrial function and oxidative stress. The objective of the study was to determine whether mitochondrial function, content, and oxidative stress differ in well-matched obese individuals in the upper [obese diet sensitive (ODS)] vs lower quintiles [obese diet resistant (ODR)] for rate of weight loss. Primary myotubes derived from muscle biopsies of individuals identified as ODS or ODR were studied. Compliant ODS and ODR females who completed in the Ottawa Hospital Weight Management Program and identified as ODS and ODR participated in this study. Eleven ODS and nine ODR weight-stable females matched for age, body mass, and body mass index participated in this study. Vastus lateralis muscle biopsies were obtained and processed for muscle satellite cell isolation. Mitochondrial respiration, content, reactive oxygen species, and glutathione redox ratios were measured...
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Research Interests: Obesity, Low back pain, Humans, Program Development, Back Pain, and 15 moreFemale, Male, Exercise, Body Mass Index, Clinical Sciences, Aged, Middle Aged, Adult, Interdisciplinary Communication, Pilot Projects, Neurosciences, Pain Measurement, Ambulatory Care, Disability Evaluation, and diet reducing
Research Interests: Obesity, Biology, Medicine, Biological Sciences, Insulin Resistance, and 15 moreMitochondrial DNA, Humans, Female, Male, Physical sciences, Superoxide Dismutase, Clinical Sciences, Middle Aged, Elsevier, Type 2 Diabetes Mellitus, Protons, Biochemistry and cell biology, Case Control Studies, Medical biochemistry and metabolomics, and Muscle fibers skeletal
Insulin resistance may be linked to incomplete fatty acid β-oxidation and the subsequent increase in acylcarnitine species in different tissues including skeletal muscle. It is not known if acylcarnitines participate in muscle insulin... more
Insulin resistance may be linked to incomplete fatty acid β-oxidation and the subsequent increase in acylcarnitine species in different tissues including skeletal muscle. It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aims of this study were to determine whether acylcarnitines can elicit muscle insulin resistance and to better understand the link between incomplete muscle fatty acid β-oxidation, oxidative stress, inflammation, and insulin-resistance development. Differentiated C2C12, primary mouse, and human myotubes were treated with acylcarnitines (C4:0, C14:0, C16:0) or with palmitate with or without carnitine acyltransferase inhibition by mildronate. Treatment with C4:0, C14:0, and C16:0 acylcarnitines resulted in 20-30% decrease in insulin response at the level of Akt phosphorylation and/or glucose uptake. Mildronate reversed palmitate-induced insulin resistance concomitant with an ∼25% decrease in short-chain acylcarnitine and acetylcarnitine secretion. Although proinflammatory cytokines were not affected under these conditions, oxidative stress was increased by 2-3 times by short- or long-chain acylcarnitines. Acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Results are consistent with the conclusion that incomplete muscle fatty acid β-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance.
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Understanding the metabolic factors that contribute to obesity development and weight loss success are critical for combating obesity and obesity-related disorders. This review provides an overview of energy metabolism with a particular... more
Understanding the metabolic factors that contribute to obesity development and weight loss success are critical for combating obesity and obesity-related disorders. This review provides an overview of energy metabolism with a particular focus on mitochondrial function in health and in obesity. Mitochondrial proton leak contributes significantly to whole body energy expenditure and the potential role of energy uncoupling in weight loss success is discussed. We provide evidence to support the hypothesis that differences in energy efficiency are important regulators of body weight and weight loss success.