Ottawa Hospital Weight Management Clinic

Ottawa, Canada

Ottawa Hospital Weight Management Clinic

Ottawa, Canada

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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.


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.


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.


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.


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.


Aguer C.,University of Ottawa | Pasqua M.,University of Ottawa | Thrush A.B.,University of Ottawa | Moffat C.,University of Ottawa | And 7 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Muscle insulin resistance is linked to oxidative stress and decreased mitochondrial function. However, the exact cause of muscle insulin resistance is still unknown. Since offspring of patients with type 2 diabetes mellitus (T2DM) are susceptible to developing insulin resistance, they are ideal for studying the early development of insulin resistance. By using primary muscle cells derived from obese non-diabetic subjects with (FH. +) or without (FH. -) a family history of T2DM, we aimed to better understand the link between mitochondrial function, oxidative stress, and muscle insulin resistance. Insulin-stimulated glucose uptake and glycogen synthesis were normal in FH. + myotubes. Resting oxygen consumption rate was not different between groups. However, proton leak was higher in FH. + myotubes. This was associated with lower ATP content and decreased mitochondrial membrane potential in FH. + myotubes. Surprisingly, mtDNA content was higher in FH. + myotubes. Oxidative stress level was not different between FH. + and FH. - groups. Reactive oxygen species content was lower in FH. + myotubes when differentiated in high glucose/insulin (25. mM/150. pM), which could be due to higher oxidative stress defenses (SOD2 expression and uncoupled respiration). The increased antioxidant defenses and mtDNA content in FH. + myotubes suggest the existence of compensatory mechanisms, which may provisionally prevent the development of insulin resistance. © 2013 Elsevier B.V.


Roffey D.M.,Ottawa Hospital Research Institute | Roffey D.M.,University of Ottawa | Ashdown L.C.,University of Ottawa | Dornan H.D.,University of Ottawa | And 6 more authors.
Spine Journal | Year: 2011

Background context: Low back pain (LBP) is a prevalent and costly condition. Although its etiology is largely unknown, a link to obesity is suspected, and weight loss programs are often recommended to obese patients with LBP. Purpose: To assess the efficacy of a pilot, multidisciplinary, medically supervised, nonsurgical weight loss program involving meal replacement, caloric restriction, education, exercise, and group therapy at reducing the severity of LBP in obese adults. Study design: Pilot prospective cohort study. Patient sample: A total of 46 obese adults (mean body mass index [BMI] 44.7±7.6 kg/m2) referred to an academic hospital for a multidisciplinary, medically supervised, nonsurgical weight loss program who reported LBP were enrolled. Outcome measures: The severity of LBP was measured using the Numerical Pain Scale (NPS) and modified Oswestry Disability Index (ODI) at baseline (Week 1), Week 14, and Week 53; weight, BMI, dietary adherence, and physical activity levels were also measured. Methods: The 52-week weight loss program was administered by a team of physicians, dieticians, exercise specialists, and nurses and included liquid meal replacements for 12 weeks, followed by supervised caloric restriction diets for 13 weeks. Participants also attended weekly group therapy and educational meetings for the first 26 weeks, after which they were instructed to continue caloric restriction diets, engage in 60 to 90 minutes of daily physical activity, and attend monthly group meetings for an additional 26 weeks. Results: At baseline, NPS was mild in 61% (n=28), moderate in 30% (n=14), and severe in 9% (n=4), whereas ODI was moderate in 48% (n=22), severe in 17% (n=8), and crippling in 4% (n=2). At Week 14 (n=42; 92% follow-up), there were significant improvements in NPS (p=.001) and ODI (p=.0005), and significant weight loss (p<.0001). At Week 53 (n=28; 61% follow-up), there was a trend toward improvement in NPS (p=.07), significant improvement in ODI (p=.0009), and significant weight loss (p=.0005); reduction in BMI was significantly associated with clinically important improvements in ODI (p=.046). Conclusions: This pilot prospective cohort study suggests that a 52-week multidisciplinary, medically supervised, nonsurgical weight loss program in obese patients with LBP improved both pain and function. © 2011 Elsevier Inc. All rights reserved.


Aguer C.,University of Ottawa | Gambarotta D.,University of Ottawa | Mailloux R.J.,University of Ottawa | Moffat C.,University of Ottawa | And 3 more authors.
PLoS ONE | Year: 2011

Background: Human primary myotubes are highly glycolytic when cultured in high glucose medium rendering it difficult to study mitochondrial dysfunction. Galactose is known to enhance mitochondrial metabolism and could be an excellent model to study mitochondrial dysfunction in human primary myotubes. The aim of the present study was to 1) characterize the effect of differentiating healthy human myoblasts in galactose on oxidative metabolism and 2) determine whether galactose can pinpoint a mitochondrial malfunction in post-diabetic myotubes. Methodology/Principal Findings: Oxygen consumption rate (OCR), lactate levels, mitochondrial content, citrate synthase and cytochrome C oxidase activities, and AMPK phosphorylation were determined in healthy myotubes differentiated in different sources/concentrations of carbohydrates: 25 mM glucose (high glucose (HG)), 5 mM glucose (low glucose (LG)) or 10 mM galactose (GAL). Effect of carbohydrates on OCR was also determined in myotubes derived from post-diabetic patients and matched obese non-diabetic subjects. OCR was significantly increased whereas anaerobic glycolysis was significantly decreased in GAL myotubes compared to LG or HG myotubes. This increased OCR in GAL myotubes occurred in conjunction with increased cytochrome C oxidase activity and expression, as well as increased AMPK phosphorylation. OCR of post-diabetic myotubes was not different than that of obese non-diabetic myotubes when differentiated in LG or HG. However, whereas GAL increased OCR in obese non-diabetic myotubes, it did not affect OCR in post-diabetic myotubes, leading to a significant difference in OCR between groups. The lack of an increase in OCR in post-diabetic myotubes differentiated in GAL was in relation with unaltered cytochrome C oxidase activity levels or AMPK phosphorylation. Conclusions/Significance: Our results indicate that differentiating human primary myoblasts in GAL enhances aerobic metabolism. Because this cell culture model elicited an abnormal response in cells from post-diabetic patients, it may be useful in further studies of the molecular mechanisms of mitochondrial dysfunction. © 2011 Aguer et al.


Antoun G.,University of Ottawa | McMurray F.,University of Ottawa | Thrush A.B.,University of Ottawa | Patten D.A.,University of Ottawa | And 5 more authors.
Diabetologia | Year: 2015

Aims/hypothesis: Skeletal muscle mitochondrial dysfunction has been documented in patients with type 2 diabetes mellitus; however, specific respiratory defects and their mechanisms are poorly understood. The aim of the current study was to examine oxidative phosphorylation and electron transport chain (ETC) supercomplex assembly in rectus abdominis muscles of 10 obese diabetic and 10 obese non-diabetic individuals. Methods: Twenty obese women undergoing Roux-en-Y gastric bypass surgery were recruited for this study. Muscle samples were obtained intraoperatively and subdivided for multiple analyses, including high-resolution respirometry and assessment of supercomplex assembly. Clinical data obtained from referring physicians were correlated with laboratory findings. Results: Participants in both groups were of a similar age, weight and BMI. Mitochondrial respiration rates were markedly reduced in diabetic vs non-diabetic patients. This defect was observed during maximal ADP-stimulated respiration in the presence of complex I-linked substrates and complex I- and II-linked substrates, and during maximal uncoupled respiration. There were no differences in fatty acid (octanoyl carnitine) supported respiration, leak respiration or isolated activity of cytochrome c oxidase. Intriguingly, significant correlations were found between glycated haemoglobin (HbA1c) levels and maximal respiration or respiration supported by complex I, complex I and II or fatty acid. In the muscle of diabetic patients, blue native gel electrophoresis revealed a striking decrease in complex I, III and IV containing ETC supercomplexes. Conclusions/interpretation: These findings support the hypothesis that ETC supercomplex assembly may be an important underlying mechanism of muscle mitochondrial dysfunction in type 2 diabetes mellitus. © 2015, Springer-Verlag Berlin Heidelberg.


Thrush A.B.,University of Ottawa | Dent R.,Ottawa Hospital Weight Management Clinic | McPherson R.,University of Ottawa | Harper M.-E.,University of Ottawa
FEBS Journal | Year: 2013

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. © 2013 FEBS.

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