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Ghosh S.,North Carolina Central University | Dent R.,Ottawa Hospital Weight Management Clinic | Harper M.E.,University of Ottawa | Stuart J.,Glaxosmithkline | McPherson R.,University of Ottawa
Obesity | Year: 2011

Weight loss in response to caloric restriction displays significant interindividual heterogeneity. To develop early predictors of weight-loss success, we have compared whole-blood gene expression profiles of obese, diet-sensitive vs. obese, diet-resistant subjects prior to the initiation of clinically supervised caloric restriction. Pathway enrichment analysis of gene expression profiles by multiple applications converged on the oxidative phosphorylation (OXPHOS) pathway, and to a lesser extent the proteasome pathway, as statistically significantly upregulated in obese, diet-sensitive subjects compared to the diet-resistant subjects. The finding of increased OXPHOS is consistent with earlier observations of increased proton leak, increased expression of OXPHOS genes, and increased oxidative muscle fibers in skeletal muscle of obese, diet-sensitive subjects. The current study further highlights the utility of blood as a sentinel tissue reflecting systemic states and provides a potential modality to predict future weight-loss success, relevant to the design of individualized bariatric treatment programs. © 2010 The Obesity Society. Source

Ghosh S.,North Carolina Central University | Dent R.,Ottawa Hospital Weight Management Clinic | Harper M.-E.,University of Ottawa | Gorman S.A.,Glaxosmithkline | And 2 more authors.
BMC Medical Genomics | Year: 2010

Background. Obesity is reaching epidemic proportions and represents a significant risk factor for cardiovascular disease, diabetes, and cancer. Methods. To explore the relationship between increased body mass and gene expression in blood, we conducted whole-genome expression profiling of whole blood from seventeen obese and seventeen well matched lean subjects. Gene expression data was analyzed at the individual gene and pathway level and a preliminary assessment of the predictive value of blood gene expression profiles in obesity was carried out. Results. Principal components analysis of whole-blood gene expression data from obese and lean subjects led to efficient separation of the two cohorts. Pathway analysis by gene-set enrichment demonstrated increased transcript levels for genes belonging to the "ribosome", "apoptosis" and "oxidative phosphorylation" pathways in the obese cohort, consistent with an altered metabolic state including increased protein synthesis, enhanced cell death from proinflammatory or lipotoxic stimuli, and increased energy demands. A subset of pathway-specific genes acted as efficient predictors of obese or lean class membership when used in Naive Bayes or logistic regression based classifiers. Conclusion. This study provides a comprehensive characterization of the whole blood transcriptome in obesity and demonstrates that the investigation of gene expression profiles from whole blood can inform and illustrate the biological processes related to regulation of body mass. Additionally, the ability of pathway-related gene expression to predict class membership suggests the feasibility of a similar approach for identifying clinically useful blood-based predictors of weight loss success following dietary or surgical interventions. © 2010 Ghosh et al; licensee BioMed Central Ltd. Source

Thrush A.B.,University of Ottawa | Zhang R.,University of Ottawa | Chen W.,University of Ottawa | Seifert E.L.,University of Ottawa | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Results: Mitochondrial proton leak was increased in myotubes of ODS compared with ODR (P< .05). Reduced and oxidized glutathione was decreased in the myotubes of ODR vs ODS (P< .05), indicating a more oxidized glutathione redox state. There were no differences in myotube mitochondrial content, uncoupling protein 3, or adenine nucleotide translocase levels.Conclusions: Lower rate of mitochondrial proton leak in muscle is a cell autonomous phenomenon in ODR vs ODS individuals, and this is associated with a more oxidized glutathione redox state in ODR vs ODS myotubes. The muscle of ODR subjects may thus have a lower capacity to adapt to oxidative stress as compared with ODS.Context: 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.Objective: 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.Design: Primary myotubes derived from muscle biopsies of individuals identified as ODS or ODR were studied.Setting: Compliant ODS and ODR females who completed in the Ottawa Hospital Weight Management Program and identified as ODS and ODR participated in this study.Patients or Other Participants: Eleven ODS and nine ODR weight-stable females matched for age, body mass, and body mass index participated in this study.Intervention: Vastus lateralis muscle biopsies were obtained and processed for muscle satellite cell isolation.Main Outcome Measures: Mitochondrial respiration, content, reactive oxygen species, and glutathione redox ratios were measured in the myotubes of ODS and ODR individuals. Copyright © 2014 by the Endocrine Society. Source

Aguer C.,University of Ottawa | McCoin C.S.,University of California at Davis | McCoin C.S.,Obesity and Metabolism Research Unit | Knotts T.A.,Obesity and Metabolism Research Unit | And 11 more authors.
FASEB Journal | Year: 2015

Insulin resistance may be linked to incomplete fatty acid b-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. © FASEB. Source

Gerrits M.F.,University of Ottawa | Ghosh S.,North Carolina Central University | Kavaslar N.,University of Ottawa | Hill B.,University of Ottawa | And 8 more authors.
Journal of Lipid Research | Year: 2010

Inter-individual variability in weight gain and loss under energy surfeit and deficit conditions, respectively, are well recognized but poorly understood phenomena. We documented weight loss variability in an intensively supervised clinical weight loss program and assessed skeletal muscle gene expression and phenotypic characteristics related to variable response to a 900 kcal regimen. Matched pairs of healthy, diet-compliant, obese diet-sensitive (ODS) and diet-resistant (ODR) subjects were defined as those in the highest and lowest quintiles for weight loss rate. Physical activity energy expenditure was minimal and comparable. Following program completion and weight stabilization, skeletal muscle biopsies were obtained. Gene expression analysis of rectus femoris and vastus lateralis indicated upregulation of genes and gene sets involved in oxidative phosphorylation and glucose and fatty acid metabolism in ODS compared with ODR. In vastus lateralis, there was a higher proportion of oxidative (type I) fibers in ODS compared with ODR women and lean controls, fiber hypertrophy in ODS compared with ODR women and lean controls, and lower succinate dehydrogenase in oxidative and oxidative-glycolytic fibers in all obese compared with lean subjects. Intramuscular lipid content was generally higher in obese versus lean, and specifically higher in ODS vs. lean women.jlr Altogether, our findings demonstrate differences in muscle gene expression and fiber composition related to clinical weight loss success. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc. Source

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