IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes.

Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.

The weapons of mass destruction-civil support team PA.

ABSTRACT: The weapons of mass destruction-civil support team (WMD-CST) physician associate/assistant (PA) is an autonomous PA who balances military and civilian roles to achieve mission success and support the safety of the US public. This article by multiple WMD-CST PAs across the nation describes the WMD-CST PA profession and how traditional PA roles continue to advance.

Targeting skeletal muscle mitochondrial health in obesity.

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.

A fully joint Bayesian quantitative trait locus mapping of human protein abundance in plasma.

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) synthetic data emulating the real data show how LOCUS borrows strength across correlated protein levels and markers on a genome-wide scale to effectively increase statistical power. Notably, 15% of the pQTLs uncovered by LOCUS would be missed by the univariate approach, including several trans and pleiotropic hits with successful independent validation. Finally, the analysis of extensive clinical data from the two cohorts indicates that the genetically-driven proteins identified by LOCUS are enriched in associations with low-grade inflammation, insulin resistance and dyslipidemia and might therefore act as endophenotypes for metabolic diseases. While considerations on the clinical role of the pQTLs are beyond the scope of our work, these findings generate useful hypotheses to be explored in future research; all results are accessible online from our searchable database. Thanks to its efficient variational Bayes implementation, LOCUS can analyze jointly thousands of traits and millions of markers. Its applicability goes beyond pQTL studies, opening new perspectives for large-scale genome-wide association and QTL analyses. Diet, Obesity and Genes (DiOGenes) trial registration number: NCT00390637.

Acylcarnitines: potential implications for skeletal muscle insulin resistance.

Insulin resistance may be linked to incomplete fatty acid ß-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 ß-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 ß-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance.

Impaired mitochondrial oxidative phosphorylation and supercomplex assembly in rectus abdominis muscle of diabetic obese individuals.

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.

Adiposity significantly modifies genetic risk for dyslipidemia.

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), GalNAc-transferase (GALNT2), endothelial lipase (LIPG), and phospholipid transfer protein (PLTP) for HDLc. In contrast, the GRSLDL cholesterol × adiposity interaction was not significant. Sexual dimorphism was evident for the GRSHDL on HDLc in obese (P(Interaction) = 0.016) but not lean subjects. SNP by BMI interactions may provide biological insight into specific genetic associations and missing heritability.

Increased proton leak and SOD2 expression in myotubes from obese non-diabetic subjects with a family history of type 2 diabetes.

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 (25mM/150pM), 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.

Excellence and evidence in staffing: a data-driven model for excellence in staffing (2nd edition).

The Patient Protection and Affordable Care Act (PPACA, 2010) and the Institute of Medicine's (IOM, 2011) Future of Nursing report have prompted changes in the U.S. health care system. This has also stimulated a new direction of thinking for the profession of nursing. New payment and priority structures, where value is placed ahead of volume in care, will start to define our health system in new and unknown ways for years. One thing we all know for sure: we cannot afford the same inefficient models and systems of care of yesterday any longer. The Data-Driven Model for Excellence in Staffing was created as the organizing framework to lead the development of best practices for nurse staffing across the continuum through research and innovation. Regardless of the setting, nurses must integrate multiple concepts with the value of professional nursing to create new care and staffing models. Traditional models demonstrate that nurses are a commodity. If the profession is to make any significant changes in nurse staffing, it is through the articulation of the value of our professional practice within the overall health care environment. This position paper is organized around the concepts from the Data-Driven Model for Excellence in Staffing. The main concepts are: Core Concept 1: Users and Patients of Health Care, Core Concept 2: Providers of Health Care, Core Concept 3: Environment of Care, Core Concept 4: Delivery of Care, Core Concept 5: Quality, Safety, and Outcomes of Care. This position paper provides a comprehensive view of those concepts and components, why those concepts and components are important in this new era of nurse staffing, and a 3-year challenge that will push the nursing profession forward in all settings across the care continuum. There are decades of research supporting various changes to nurse staffing. Yet little has been done to move that research into practice and operations. While the primary goal of this position paper is to generate research and innovative thinking about nurse staffing across all health care settings, a second goal is to stimulate additional publications. This includes a goal of at least 20 articles in Nursing Economic$ on best practices in staffing and care models from across the continuum over the next 3 years.

A comparison of virtual and in person delivery of a full meal replacement program for obesity.

Objective: Full meal replacement (FMR) Intensive Lifestyle Interventions (ILI) have been used for weight management. However, predictors of efficacy with these programs are less clear. The primary objective was to assess weight loss predictors in a community-based FMR ILI program. A secondary objective was to determine if weight loss was different between virtual and in person ILI. Methods: This was a retrospective cohort study involving 234 patients who started the program between 1 January 2016 and 3 March 2021. In the 24-week program, patients spent 12 weeks on FMR and then transitioned back to food for the remainder, with weekly follow up with a physician and group sessions with a dietitian. Visits were in person prior to March 2020 and virtual afterward. Results: Patients' average age was 47.5 years (SD = 12.0) and 73.5% were female. Average weight loss was 14.3% (SD = 6.2%). There was no significant difference in weight loss between virtual and in person programs. Patients on a Glucagon-like Peptide-1 Receptor Agonist prior lost less weight. Other significant associations between groups were baseline Hemoglobin A1C, classes attended, as well as the age since peak weight. Conclusion: Weight loss from virtual ILI was not significantly different from person ILI. More research is needed to determine how to best stratify care as virtual or in person using FMR programs.

Validity of two weight prediction models for community-living patients participating in a weight loss program.

Models predicting individual body weights over time clarify patient expectations in weight loss programs. The accuracy of two commonly used weight prediction models in community living people is unclear. All eligible people entering a weight management program between 1992 and 2015 were included. Patients' diet was 1200 kcal/day for week 0 followed by 900 kcal/day for weeks 1-7 and were excluded from the analysis if they were nonadherent. We generated expected weights using the National Institutes of Health Body Weight Planner (NIH-BWP) and the Pennington Biomedical Research Center Weight Loss Predictor (PBRC-WLP). 3703 adherent people were included (mean age 46 years, 72.6% women, mean [SD] weight 262.3 pounds [54.2], mean [SD] BMI 42.4 [7.6]). Mean (SD) relative body weight differences (100*[observed-expected]/expected) for NIH-BWP and PBRC-WLP models was - 1.5% (3.8) and - 2.9% (3.2), respectively. At week 7, mean squared error with NIH-BWP (98.8, 83%CI 89.7-108.8) was significantly lower than that with PBRC-WLP (117.7, 83%CI 112.4-123.4). Notable variation in relative weight difference were seen (for NIH-BWP, 5th-95th percentile was - 6.2%, + 3.7%; Δ 9.9%). During the first 7 weeks of a weight loss program, both weight prediction models returned expected weights that were very close to observed values with the NIH-BWP being more accurate. However, notable variability between expected and observed weights in individual patients were seen. Clinicians can monitor patients in weight loss programs by comparing their progress with these data.

Combating Fentanyl: National Guard Physician Assistants on the Front Lines of America's War Against Synthetic Opioids.

There is a significant threat to global health security due to synthetic opioids, illicitly manufactured fentanyl (IMF), and nefarious uses of pharmaceutical based agents (PBA). Since 2014, increased distribution of synthetic opioids including IMF into the US through China, India, and Mexico has resulted in devastating consequences to the average street drug user. Additionally, clandestine lab operations for pill manufacturing and distribution have increased, along with unintentional drug overdoses due to drugs being laced with fentanyl or some other synthetic opioid derivative. Naloxone has been shown to be an effective and useful tool for reversing signs and symptoms of synthetic opioid overdose, though additional doses may be required depending on the analog. In addition to the risk of overdose in US civilians, other state actors have utilized fentanyl and its analogs as incapacitants resulting in significant numbers of casualties. The National Guard Weapons of Mass Destruction-Civil Support Teams (WMD-CST) have been on the front lines supporting federal law enforcement agencies with hazard identification and assessment. Physician Assistants (PA) are assigned to these units and provide the necessary skills and expertise to keep on scene personnel safe. This article aims to dispel some of the rumors and myths surrounding fentanyl in an effort to educate first receivers, first responders, and hospital providers. Lastly, this article provides a review of synthetic opioid production, overdose, hazards, treatment/countermeasures, decontamination for responders, and the potential use of synthetic opioids as WMDs.

Does the Presence of Type 2 Diabetes or Metabolic Syndrome Impact Reduction in Waist Circumference During Weight Loss?

OBJECTIVES: Our aim in this study was to compare the change in waist circumference given the same degree of weight loss in patients who meet the criteria for metabolic syndrome or type 2 diabetes and those who do not meet these criteria. Because visceral adiposity is a key feature of both conditions and intra-abdominal adipocytes show higher lipolytic activity, we sought to determine whether changes in waist circumference differed in individuals with and without these conditions. METHODS: The Ottawa Hospital Weight Management Clinic offers a course in lifestyle modification and uses 12 weeks of total meal replacement. We compared the decrease in waist circumference between patients with metabolic syndrome or diabetes and those without these conditions who had lost a similar amount of weight using measurements from the first 6 weeks of meal replacement. RESULTS: We evaluated 3,559 patients who attended the program between September 1992 and April 2015. The patient population was largely Caucasian and of European descent and all meetings were face to face. The mean weight loss for men was 15.1±20.2 kg, and the mean weight loss for women was 9.7±2.4 kg. There were no significant differences in decrease in waist circumference between those with and without metabolic syndrome in both men (11.7±3.9 cm vs 11.4±3.8 cm, p=0.48) and women (9.0±3.6 cm vs 9.1±3.7 cm, p=0.26). CONCLUSIONS: Our results show that, given the same degree of weight loss, patients with and without diabetes or metabolic syndrome experience a similar change in waist circumference.

Appetite Changes in Weight Regain and Weight Maintenance After Roux-en-Y Gastric Bypass.

PURPOSE: Roux-en-Y gastric bypass (RYGB) surgery produces significant weight loss. However, a number of patients experience weight regain years after surgery. Factors driving weight regain after surgical interventions are currently being explored. Our objective was to investigate appetite-related measures associated with weight regain after RYGB surgery. MATERIALS AND METHODS: Using a cross-sectional design, 29 participants (49.6 ± 9.1 years of age; current BMI 32.4 ± 4.7 kg/m2, 43.6 ± 8.9 months post-RYGB) were stratified into tertiles according to weight regain per month after nadir (weight maintenance (WM), n = 9; low weight regain (LWR), n = 10; and high weight regain (HWR), n = 10). The average weight regain was, by design, significantly different between the groups (WM = 2.2 ± 2.5 kg; LWR = 10.0 ± 3.4 kg; HWR = 14.9 ± 6.3 kg regained, p < 0.05). Appetite (visual analog scales), olfactory performance ("sniffin sticks"), eating behaviors (Three Factor Eating Questionnaire), food reward (Leeds Food Preference Questionnaire), and appetite-related hormones (ghrelin, PYY, GLP-1 and leptin) were measured fasting and in response to a standardized test meal. RESULTS: Dietary restraint was significantly higher than clinical cutoffs in WM and LWR (p < 0.05). As expected, significant time effects were noted for ghrelin, PYY, and GLP-1, but there were no group differences. CONCLUSION: The results suggest that appetite-related outcomes are similar across individuals who have maintained weight loss and experienced regain following RYGB.

Association of muscle fiber type with measures of obesity: A systematic review.

Obesity derives from an extended period of positive energy imbalance due to a complex interplay of environmental and biological factors. Muscle fiber type and physiology have been hypothesized to affect metabolism and energy expenditure and thus to affect an individual's propensity to gain weight. However, there have been conflicting reports regarding a relationship between muscle fiber type and obesity. Here, we systematically reviewed literature investigating this topic from PubMed, Web of Science, and EMBASE. Of these, 32 articles were included in our final review and analysis. Most studies (22/32) reported a significant relationship between muscle fiber-type proportion and a measure of obesity. Overall, there was a significant negative relationship between the proportion of type I fibers and body mass index (BMI) and a significant positive relationship between the proportion of type IIX fibers and BMI. Moreover, between-group comparisons indicated a greater prevalence of type IIX fibers and a lower prevalence of type I fibers in patients living with obesity relative to lean individuals. These significant relationships were confirmed in a meta-analysis of these data. The causal nature of these associations remains to be evaluated.

Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity.

BACKGROUND: Current paradigms for predicting weight loss in response to energy restriction have general validity but a subset of individuals fail to respond adequately despite documented diet adherence. Patients in the bottom 20% for rate of weight loss following a hypocaloric diet (diet-resistant) have been found to have less type I muscle fibres and lower skeletal muscle mitochondrial function, leading to the hypothesis that physical exercise may be an effective treatment when diet alone is inadequate. In this study, we aimed to assess the efficacy of exercise training on mitochondrial function in women with obesity with a documented history of minimal diet-induced weight loss. METHODS: From over 5000 patient records, 228 files were reviewed to identify baseline characteristics of weight loss response from women with obesity who were previously classified in the top or bottom 20% quintiles based on rate of weight loss in the first 6 weeks during which a 900 kcal/day meal replacement was consumed. A subset of 20 women with obesity were identified based on diet-resistance (n=10) and diet sensitivity (n=10) to undergo a 6-week supervised, progressive, combined aerobic and resistance exercise intervention. FINDINGS: Diet-sensitive women had lower baseline adiposity, higher fasting insulin and triglycerides, and a greater number of ATP-III criteria for metabolic syndrome. Conversely in diet-resistant women, the exercise intervention improved body composition, skeletal muscle mitochondrial content and metabolism, with minimal effects in diet-sensitive women. In-depth analyses of muscle metabolomes revealed distinct group- and intervention- differences, including lower serine-associated sphingolipid synthesis in diet-resistant women following exercise training. INTERPRETATION: Exercise preferentially enhances skeletal muscle metabolism and improves body composition in women with a history of minimal diet-induced weight loss. These clinical and metabolic mechanism insights move the field towards better personalised approaches for the treatment of distinct obesity phenotypes. FUNDING: Canadian Institutes of Health Research (CIHR-INMD and FDN-143278; CAN-163902; CIHR PJT-148634).

Association of functionally significant Melanocortin-4 but not Melanocortin-3 receptor mutations with severe adult obesity in a large North American case-control study.

Functionally significant heterozygous mutations in the Melanocortin-4 receptor (MC4R) have been implicated in 2.5% of early onset obesity cases in European cohorts. The role of mutations in this gene in severely obese adults, particularly in smaller North American patient cohorts, has been less convincing. More recently, it has been proposed that mutations in a phylogenetically and physiologically related receptor, the Melanocortin-3 receptor (MC3R), could also be a cause of severe human obesity. The objectives of this study were to determine if mutations impairing the function of MC4R or MC3R were associated with severe obesity in North American adults. We studied MC4R and MC3R mutations detected in a total of 1821 adults (889 severely obese and 932 lean controls) from two cohorts. We systematically and comparatively evaluated the functional consequences of all mutations found in both MC4R and MC3R. The total prevalence of rare MC4R variants in severely obese North American adults was 2.25% (CI(95%): 1.44-3.47) compared with 0.64% (CI(95%): 0.26-1.43) in lean controls (P < 0.005). After classification of functional consequence, the prevalence of MC4R mutations with functional alterations was significantly greater when compared with controls (P < 0.005). In contrast, the prevalence of rare MC3R variants was not significantly increased in severely obese adults [0.67% (CI(95%): 0.27-1.50) versus 0.32% (CI(95%): 0.06-0.99)] (P = 0.332). Our results confirm that mutations in MC4R are a significant cause of severe obesity, extending this finding to North American adults. However, our data suggest that MC3R mutations are not associated with severe obesity in this population.

Epigenome-Wide Study Identified Methylation Sites Associated with the Risk of Obesity.

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 rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC, ADCY3 and DNAJC27. In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.

Distinct skeletal muscle fiber characteristics and gene expression in diet-sensitive versus diet-resistant obesity.

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. Altogether, our findings demonstrate differences in muscle gene expression and fiber composition related to clinical weight loss success.