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 b-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 palmitateinduced 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 b-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance.-Aguer, C., McCoin, C. S., Knotts, T. A., Thrush, A. B., Ono-Moore, K., McPherson, R., Dent, R., Hwang, D. H., Adams, S. H., Harper, M.-E. Acylcarnitines: potential implications for skeletal muscle insulin resistance. FASEB J. 29, 336-345 (2015). www.fasebj.org

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 (HbA 1c ) 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.

Obesity is reaching epidemic proportions in developed countries and represents a signifi cant risk factor for cardiovascular disease, diabetes, and cancer ( 1 ). Enrolment in clinical and nonclinical obesity treatment programs is unprecedented. Success in obesity treatment programs is highly variable, related in part to compliance and program characteristics (e.g., type and duration of hypocaloric diets, educational components, and/or exercise-associated energy expenditure). While it is generally well accepted that there is substantial inter-individual variability in the susceptibility to weight gain in response to overfeeding ( 2, 3 ), less well understood is the impact of biological factors on weight loss success. However, studies of monozygotic twins have shown greater inter-pair than intra-pair variation in weight loss ( 4 ), consistent with the idea that there are important genetic determinants of weight loss success. We have studied the molecular and cellular determinants of variable weight loss in highly compliant subjects in an intensively supervised and interactive hypocaloric clinical obesity treatment program at the Ottawa Hospital. We previously reported differences in muscle mitochondrial energy ineffi ciencies between program participants exhibiting high versus low weight loss success ( 5 ). Here, we extend these fi ndings by demonstrating distinct differences in skeletal muscle gene expression profi les and in structural and metabolic characteristics between individuals who Abstract Inter-individual variability in weight gain and loss under energy surfeit and defi cit 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 dietresistant (ODR) subjects were defi ned 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) fi bers in ODS compared with ODR women and lean controls, fi ber hypertrophy in ODS compared with ODR women and lean controls, and lower succinate dehydrogenase in oxidative and oxidative-glycolytic fi bers in all obese compared with lean subjects. Intramuscular lipid content was generally higher in obese versus lean, and specifi cally higher in ODS vs. lean women. Altogether, our fi ndings demonstrate differences in muscle gene expression and fi ber composition related to clinical weight loss success. Abbreviations: B...

BackgroundObesity is reaching epidemic proportions and represents a significant risk factor for cardiovascular disease, diabetes, and cancer.MethodsTo 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.ResultsPrincipal 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.ConclusionThis 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.

IntroductionPsychotropic medication use is associated with weight gain. While there are studies and reviews comparing weight gain for psychotropics within some classes, clinicians frequently use drugs from different classes to treat psychiatric disorders.ObjectiveTo undertake a systematic review of all classes of psychotropics to provide an all encompassing evidence-based tool that would allow clinicians to determine the risks of weight gain in making both intra-class and interclass choices of psychotropics.Methodology and ResultsWe developed a novel hierarchical search strategy that made use of systematic reviews that were already available. When such evidence was not available we went on to evaluate randomly controlled trials, followed by cohort and other clinical trials, narrative reviews, and, where necessary, clinical opinion and anecdotal evidence. The data from the publication with the highest level of evidence based on our hierarchical classification was presented. Recommendations from an expert panel supplemented the evidence used to rank these drugs within their respective classes. Approximately 9500 articles were identified in our literature search of which 666 citations were retrieved. We were able to rank most of the psychotropics based on the available evidence and recommendations from subject matter experts. There were few discrepancies between published evidence and the expert panel in ranking these drugs.ConclusionPotential for weight gain is an important consideration in choice of any psychotropic. This tool will help clinicians select psychotropics on a case-by-case basis in order to minimize the impact of weight gain when making both intra-class and interclass choices.