Identification of factors associated with sarcopenic obesity development: Literature review and expert panel voting.

Sarcopenic obesity (SO) is defined as the combination of excess fat mass (obesity) and low skeletal muscle mass and function (sarcopenia). The identification and classification of factors related to SO would favor better prevention and diagnosis. The present article aimed to (i) define a list of factors related with SO based on literature analysis, (ii) identify clinical conditions linked with SO development from literature search and (iii) evaluate their relevance and the potential research gaps by consulting an expert panel. From 4746 articles screened, 240 articles were selected for extraction of the factors associated with SO. Factors were classified according to their frequency in the literature. Clinical conditions were also recorded. Then, they were evaluated by a panel of expert for evaluation of their relevance in SO development. Experts also suggested additional factors. Thirty-nine unique factors were extracted from the papers and additional eleven factors suggested by a panel of experts in the SO field. The frequency in the literature showed insulin resistance, dyslipidemia, lack of exercise training, inflammation and hypertension as the most frequent factors associated with SO whereas experts ranked low spontaneous physical activity, protein and energy intakes, low exercise training and aging as the most important. Although literature and expert panel presented some differences, this first list of associated factors could help to identify patients at risk of SO. Further work is needed to confirm the contribution of factors associated with SO among the population overtime or in randomized controlled trials to demonstrate causality.

Tuberculosis and malnutrition: The European perspective.

Tuberculosis (TB) is a leading infectious cause of death worldwide, despite ongoing efforts to limit its incidence and mortality. Although the European Region has made gains in TB incidence and mortality, it now contends with increasing numbers of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). Malnutrition is a major contributor to the burden of TB and may also be directly caused or enhanced by the onset of TB. The presence of malnutrition may worsen TB and MDR/RR-TB related treatment outcomes and contribute to growing TB drug-resistance. Preventing and treating all forms of malnutrition is an important tool to limit the spread of TB worldwide and improve TB outcomes and treatment efficacy. We carried out a scoping review of the existing evidence that addresses malnutrition in the context of TB. Our review found malnutrition increased the risk of developing TB in high-burden settings and increased the likelihood of developing unfavorable treatment outcomes, including treatment failure, loss to follow-up, and death. The potential impact of nutritional care and improved nutritional status on patient prognosis was more difficult to evaluate due to heterogeneity of patient populations, treatment protocols, and treatment durations and goals. High-quality trials that consider malnutrition as a major risk factor and relevant treatment target when designing effective strategies to limit TB spread and mortality are needed to inform evidence-based practice. In TB patients, we suggest that widespread and regular nutritional screening, assessment, and counselling, has the potential to increase effectiveness of TB management strategies and improve patient quality of life, overall outcomes, and survival.

Nutrition education in medical schools (NEMS) project: Promoting clinical nutrition in medical schools - Perspectives from different actors.

BACKGROUND & AIMS: Nutrition education is not adequately represented in the medical curriculum, and this prompted the European Society for Clinical Nutrition and Metabolism (ESPEN) to launch the Nutrition Education in Medical Schools (NEMS) Project in 2017. The aim of this original paper was to describe the perspectives of different actors in the promotion of nutrition education in medical schools. METHODS: On 11 November 2021, an online meeting was held on this topic, where nine representatives from different backgrounds participated in the scientific programme. More than 640 participants registered to this webinar. RESULTS: The different models of Nutrition Education in Medical Schools were introduced by Prof. Cristina Cuerda (Spain) and Prof. Maurizio Muscaritoli (Italy). The students' perspective was given by Ms. Alexandra Archodoulakis (Germany) and Ms. Sila Gürbüz (Turkey), representing the European Medical Students' Association. The dietitian's perspective was given by Dr. Kirsten Berk (The Netherlands), whereas Dr. Matti Aapro (Switzerland) gave the medical doctor (oncology)'s perspective. Ms. Clare Farrand (Australia) gave the WHO perspective and Dr. Kristiina Patja (Finland) explained the healthy lifestyle teaching to medical students. Lastly, Prof. Michael Chourdakis (Greece) and Prof. Zeljko Krznaric (Croatia) hosted the round-table discussion. CONCLUSIONS: There was strong agreement among the representatives from different settings joining this ESPEN initiative that increasing nutritional knowledge and skills of young doctors is now possible and will launch a virtuous cycle that will proactively involve all the other healthcare professionals working in the nutritional field.

Nutrition education in medical schools (NEMS) project: Joining ESPEN and university point of view.

BACKGROUND & AIMS: Nutrition education is not well represented in the medical curriculum. The aim of this original paper was to describe the Nutrition Education in Medical Schools (NEMS) Project of the European Society for Clinical Nutrition and Metabolism (ESPEN). METHODS: On 19 January 2020, a meeting was held on this topic that was attended by 51 delegates (27 council members) from 34 countries, and 13 European University representatives. RESULTS: This article includes the contents of the meeting that concluded with the signing of the Manifesto for the Implementation of Nutrition Education in the Undergraduate Medical Curriculum. CONCLUSION: The meeting represented a significant step forward, moved towards implementation of nutrition education in medical education in general and in clinical practice in particular, in compliance with the aims of the ESPEN Nutrition Education Study Group (NESG).

Global Leadership Initiative on Malnutrition (GLIM): Guidance on validation of the operational criteria for the diagnosis of protein-energy malnutrition in adults.

BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM) created a consensus-based framework consisting of phenotypic and etiologic criteria to record the occurrence of malnutrition in adults. This is a minimum set of practicable indicators for use in characterizing a patient/client as malnourished, considering the global variations in screening and nutrition assessment, and to be used across different health care settings. As with other consensus-based frameworks for diagnosing disease states, these operational criteria require validation and reliability testing as they are currently based solely on expert opinion. METHODS: Several forms of validation and reliability are reviewed in the context of GLIM, providing guidance on how to conduct retrospective and prospective studies for criterion and construct validity. FINDINGS: There are some aspects of GLIM criteria which require refinement; research using large data bases can be employed to reach this goal. Machine learning is also introduced as a potential method to support identification of the best cut-points and combinations of operational criteria for use with the different forms of malnutrition, which the GLIM criteria were created to denote. It is noted as well that the validation and reliability testing need to occur in a variety of sectors, populations and with diverse persons completing the criteria. CONCLUSION: The guidance presented supports the conduct and publication of quality validation and reliability studies for GLIM.

GLIM criteria for the diagnosis of malnutrition - A consensus report from the global clinical nutrition community.

RATIONALE: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A two-step approach for the malnutrition diagnosis was selected, i.e., first screening to identify "at risk" status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSION: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re-considered every 3-5 years.

GLIM criteria for the diagnosis of malnutrition - A consensus report from the global clinical nutrition community.

RATIONALE: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A two-step approach for the malnutrition diagnosis was selected, i.e., first screening to identify "at risk" status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (non-volitional weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSION: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re-considered every 3-5 years.

Intravenous lipid infusion and total plasma fatty acids positively modulate plasma acylated ghrelin in vivo.

BACKGROUND & AIMS: Ghrelin is a gastric orexigenic hormone whose activating acylation plays a relevant role in the regulation of energy balance. Nutritional modulators of ghrelin acylation and plasma acylated ghrelin (AG) concentration remain however largely undefined. We aimed at investigating whether circulating free fatty acids (FFA) contribute to regulate plasma AG and its ratio (AG/TG) to total hormone (TG). METHODS: Plasma FFA, TG, AG and AG/TG were measured in a primary outpatient care setting in a community-based population cohort of 850 individuals (age 54 ± 10 years, M/F: 408/442) from the North-East Italy MoMa study. 150-min intravenous lipid infusions in rodents (10% lipids, 600 µl/h) were used to investigate the potential causal role of FFA in the regulation of plasma ghrelin profile. RESULTS: Plasma FFA were associated positively with AG and AG/TG while negatively with TG (P < 0.01). Associations between FFA, AG and AG/TG remained statistically significant (P < 0.02) in multiple regression analysis including HOMA insulin resistance and metabolic confounders, and both AG and AG/TG but not TG increased through plasma FFA quartiles (P < 0.01). Consistent with these findings, intravenous lipid infusion with plasma FFA elevation caused elevations of AG and AG/TG (P < 0.05) with no TG modifications. CONCLUSIONS: The current findings demonstrate a novel role for circulating FFA availability to up-regulate plasma AG, which could involve FFA-induced stimulation of ghrelin acylation.

ESPEN guidelines on definitions and terminology of clinical nutrition.

BACKGROUND: A lack of agreement on definitions and terminology used for nutrition-related concepts and procedures limits the development of clinical nutrition practice and research. OBJECTIVE: This initiative aimed to reach a consensus for terminology for core nutritional concepts and procedures. METHODS: The European Society of Clinical Nutrition and Metabolism (ESPEN) appointed a consensus group of clinical scientists to perform a modified Delphi process that encompassed e-mail communication, face-to-face meetings, in-group ballots and an electronic ESPEN membership Delphi round. RESULTS: Five key areas related to clinical nutrition were identified: concepts; procedures; organisation; delivery; and products. One core concept of clinical nutrition is malnutrition/undernutrition, which includes disease-related malnutrition (DRM) with (eq. cachexia) and without inflammation, and malnutrition/undernutrition without disease, e.g. hunger-related malnutrition. Over-nutrition (overweight and obesity) is another core concept. Sarcopenia and frailty were agreed to be separate conditions often associated with malnutrition. Examples of nutritional procedures identified include screening for subjects at nutritional risk followed by a complete nutritional assessment. Hospital and care facility catering are the basic organizational forms for providing nutrition. Oral nutritional supplementation is the preferred way of nutrition therapy but if inadequate then other forms of medical nutrition therapy, i.e. enteral tube feeding and parenteral (intravenous) nutrition, becomes the major way of nutrient delivery. CONCLUSION: An agreement of basic nutritional terminology to be used in clinical practice, research, and the ESPEN guideline developments has been established. This terminology consensus may help to support future global consensus efforts and updates of classification systems such as the International Classification of Disease (ICD). The continuous growth of knowledge in all areas addressed in this statement will provide the foundation for future revisions.

Carbohydrates and insulin resistance in clinical nutrition: Recommendations from the ESPEN expert group.

Growing evidence underscores the important role of glycemic control in health and recovery from illness. Carbohydrate ingestion in the diet or administration in nutritional support is mandatory, but carbohydrate intake can adversely affect major body organs and tissues if resulting plasma glucose becomes too high, too low, or highly variable. Plasma glucose control is especially important for patients with conditions such as diabetes or metabolic stress resulting from critical illness or surgery. These patients are particularly in need of glycemic management to help lessen glycemic variability and its negative health consequences when nutritional support is administered. Here we report on recent findings and emerging trends in the field based on an ESPEN workshop held in Venice, Italy, 8-9 November 2015. Evidence was discussed on pathophysiology, clinical impact, and nutritional recommendations for carbohydrate utilization and management in nutritional support. The main conclusions were: a) excess glucose and fructose availability may exacerbate metabolic complications in skeletal muscle, adipose tissue, and liver and can result in negative clinical impact; b) low-glycemic index and high-fiber diets, including specialty products for nutritional support, may provide metabolic and clinical benefits in individuals with obesity, insulin resistance, and diabetes; c) in acute conditions such as surgery and critical illness, insulin resistance and elevated circulating glucose levels have a negative impact on patient outcomes and should be prevented through nutritional and/or pharmacological intervention. In such acute settings, efforts should be implemented towards defining optimal plasma glucose targets, avoiding excessive plasma glucose variability, and optimizing glucose control relative to nutritional support.

Plasma total and unacylated ghrelin predict 5-year changes in insulin resistance.

BACKGROUND & AIMS: Ghrelin is a gastric hormone circulating in acylated (AG) and unacylated (UG) forms, and higher plasma total ghrelin (TG) and UG may be cross-sectionally associated with lower insulin resistance in metabolic syndrome patients. The potential value of ghrelin forms in predicting insulin resistance and its time-related changes in community-based population cohorts remains unknown. METHODS: We measured TG, AG and calculated UG (TG-AG) in 716 individuals from the North-East-Italy MoMa study (age: 55 ± 9 years, BMI: 29 ± 5 kg/m(2), M/F:349/367) to test the hypothesis that circulating TG and UG, but not AG are negatively associated with insulin resistance (HOMA). We further hypothesized that baseline TG and UG negatively predict 5-year HOMA changes in a 350-individual subgroup. RESULTS: Baseline TG and UG were associated negatively with HOMA after adjusting for gender and body mass index (BMI). Baseline gender- and BMI-adjusted TG and UG were also negatively associated with HOMA at 5-year follow-up (n = 350), and changes in TG and UG were negatively associated with changes in HOMA (P < 0.05) after adjustment for anthropometric and metabolic confounders. No statistically significant correlations were observed between AG and baseline or 5-year HOMA. CONCLUSIONS: In a North-East Italy community-based population cohort, plasma TG and UG but not AG are negatively associated with HOMA. TG and UG and their changes also independently predict 5-year HOMA changes. TG and UG are therefore novel potential modulators of insulin resistance and may contribute to predict its time-related changes in humans.

Diagnostic criteria for malnutrition - An ESPEN Consensus Statement.

OBJECTIVE: To provide a consensus-based minimum set of criteria for the diagnosis of malnutrition to be applied independent of clinical setting and aetiology, and to unify international terminology. METHOD: The European Society of Clinical Nutrition and Metabolism (ESPEN) appointed a group of clinical scientists to perform a modified Delphi process, encompassing e-mail communications, face-to-face meetings, in group questionnaires and ballots, as well as a ballot for the ESPEN membership. RESULT: First, ESPEN recommends that subjects at risk of malnutrition are identified by validated screening tools, and should be assessed and treated accordingly. Risk of malnutrition should have its own ICD Code. Second, a unanimous consensus was reached to advocate two options for the diagnosis of malnutrition. Option one requires body mass index (BMI, kg/m(2)) <18.5 to define malnutrition. Option two requires the combined finding of unintentional weight loss (mandatory) and at least one of either reduced BMI or a low fat free mass index (FFMI). Weight loss could be either >10% of habitual weight indefinite of time, or >5% over 3 months. Reduced BMI is <20 or <22 kg/m(2) in subjects younger and older than 70 years, respectively. Low FFMI is <15 and <17 kg/m(2) in females and males, respectively. About 12% of ESPEN members participated in a ballot; >75% agreed; i.e. indicated ≥7 on a 10-graded scale of acceptance, to this definition. CONCLUSION: In individuals identified by screening as at risk of malnutrition, the diagnosis of malnutrition should be based on either a low BMI (<18.5 kg/m(2)), or on the combined finding of weight loss together with either reduced BMI (age-specific) or a low FFMI using sex-specific cut-offs.

Increased density of inhibitory noradrenergic parenchymal nerve fibers in hypertrophic islets of Langerhans of obese mice.

BACKGROUND AND AIM: We sought to identify mechanisms of beta cell failure in genetically obese mice. Little is known about the role of pancreatic innervation in the progression of beta cell failure. In this work we studied adrenergic innervation, in view of its potent inhibitory effect on insulin secretion. We analyzed genetically obese ob/ob and db/db mice at different ages (6- and 15-week-old), corresponding to different compensatory stages in the course of beta cell dysfunction. 15 week-old HFD mice were also studied. METHODS AND RESULTS: All mice were characterized by measures of plasma glucose, insulin, and HOMA. After perfusion, pancreata were dissected and studied by light microscopy, electron microscopy, and morphometry. Insulin, Tyrosine Hydroxylase-positive fibers and cells and Neuropeptide Y-positive cells were scored by immunohistochemistry. Islets of obese mice showed increased noradrenergic fiber innervation, with significant increases of synaptoid structures contacting beta cells compared to controls. Noradrenergic innervation of the endocrine area in obese db/db mice tended to increase with age, as diabetes progressed. In ob/ob mice, we also detected an age-dependent trend toward increased noradrenergic innervation that, unlike in db/db mice, was unrelated to glucose levels. We also observed a progressive increase in Neuropeptide Y-immunoreactive elements localized to the islet core. CONCLUSIONS: Our data show increased numbers of sympathetic nerve fibers with a potential to convey inhibitory signals on insulin secretion in pancreatic islets of genetically obese animals, regardless of their diabetic state. The findings suggest an alternative interpretation of the pathogenesis of beta cell failure, as well as novel strategies to reverse abnormalities in insulin secretion.

Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-κB inhibitor (IκB)-nuclear factor-κB (NFκB) activation in rat muscle, in the absence of mitochondrial dysfunction.

AIMS/HYPOTHESIS: Insulin effects reportedly involve reactive oxygen species (ROS) and oxidative stress in vitro, but skeletal muscle oxidative stress is an emerging negative regulator of insulin action following high-fat feeding. NEFA may enhance oxidative stress and insulin resistance. We investigated the acute impact of insulin with or without NEFA elevation on muscle ROS generation and insulin signalling, and the potential association with altered muscle mitochondrial function. METHODS: We used hyperinsulinaemic-euglycaemic clamping, 150 min, without or with lipid infusion to modulate plasma NEFA concentration in lean rats. RESULTS: Insulin and glucose (Ins) infusion selectively enhanced xanthine oxidase-dependent muscle ROS generation. Ins with lipid infusion (Ins+NEFA) lowered whole-body glucose disposal and muscle insulin signalling, and these effects were associated with high muscle mitochondrial ROS generation and activation of the proinflammatory nuclear factor-κB inhibitor (IκB)-nuclear factor-κB (NFκB) pathway. Antioxidant infusion prevented NEFA-induced systemic insulin resistance and changes in muscle mitochondrial ROS generation, IκB-NFκB pathway and insulin signalling. Changes in insulin sensitivity and signalling were independent of changes in mitochondrial enzyme activity and ATP production, which, in turn, were not impaired by changes in ROS generation under any condition. CONCLUSIONS/INTERPRETATION: Acute muscle insulin effects include enhanced ROS generation through xanthine oxidase. Additional NEFA elevation enhances mitochondrial ROS generation, activates IκB-NFκB and reduces insulin signalling. These alterations are not associated with acute reductions in mitochondrial enzyme activity and ATP production, and are reversed by antioxidant infusion. Thus, NEFA acutely cause systemic and muscle insulin resistance by enhancing muscle oxidative stress through mitochondrial ROS generation and IκB-NFκB activation.

Diabetic nephropathy is associated with increased albumin and fibrinogen production in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Hyperfibrinogenaemia and albuminuria are cardiovascular risk factors, often coexisting in diabetic and non-diabetic people. Albuminuria in turn is associated with a compensatory albumin overproduction in non-diabetic patients. It is not known whether the presence of albuminuria in patients with type 2 diabetes mellitus is associated with greater albumin and fibrinogen production rates than in normoalbuminuric patients. SUBJECTS, MATERIALS, AND METHODS: Using leucine isotope methods, we measured fractional and absolute synthesis rates (FSR, ASR) of albumin and fibrinogen in post-absorptive type 2 diabetic patients with either normal (n=11) or increased (n=10) urinary albumin excretion. RESULTS: In albuminuric patients, albumin FSR (16.2+/-1.5%/day) and ASR (20.5+/-1.9 g/day) were greater (p<0.02 and p<0.05, respectively) than in normoalbuminuric patients (FSR=11.5+/-1.1%/day; ASR=15.7+/-1.2 g/day). Fibrinogen FSR was similar between patients with normal and increased albumin excretion, but concentration, the circulating pool and ASR of fibrinogen were 40 to 50% greater (p<0.035) in patients with albuminuria. Albuminuria was positively correlated with albumin ASR, with fibrinogen concentration, the fibrinogen pool and ASR, whereas albumin synthesis was inversely correlated with calculated oncotic pressure. CONCLUSIONS/INTERPRETATION: Synthesis of albumin and fibrinogen is upregulated in type 2 diabetic patients with increased urinary albumin excretion. Albuminuria is associated with enhanced fibrinogen and albumin synthesis.

Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle.

Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage during aging. Caloric restriction (CR) is reported to reduce oxidative stress and prolong life expectancy in rodents. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle of male rats after feeding them either a control diet or calorie-restricted diet (60% of control diet) for 36 wk to determine the potential mechanism of the beneficial effects of CR. CR enhanced the transcripts of genes involved in reactive oxygen free radical scavenging function, tissue development, and energy metabolism while decreasing expression of those genes involved in signal transduction, stress response, and structural and contractile proteins. Real-time PCR measurements confirmed the changes in transcript levels of cytochrome-c oxidase III, superoxide dismutase (SOD)1, and SOD2 that were noted by the microarray approach. Mitochondrial ATP production and citrate synthase were unaltered by the dietary changes. We conclude that CR alters transcript levels of several genes in skeletal muscle and that mitochondrial function in skeletal muscle remains unaltered by the dietary intervention. Alterations in transcripts of many genes involved in reactive oxygen scavenging function may contribute to the increase in longevity reported with CR.

Impact of high-fat diet and antioxidant supplement on mitochondrial functions and gene transcripts in rat muscle.

High-fat diets are reported to increase oxidative stress in a variety of tissues, whereas antioxidant supplementation prevents many diseases attributed to high-fat diet. Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage. We hypothesized that the effects of a high-fat diet on skeletal muscle DNA functions would be attenuated or partially reversed by antioxidant supplementation. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle from male rats after feeding one of three diets (control, high-fat diet with or without antioxidants) for 36 wk. The high-fat diet altered transcript levels of 18 genes of 800 surveyed compared with the control-fed rats. Alterations included reduced expression of genes involved in free-radical scavenging and tissue development and increased expression of stress response and signal transduction genes. The magnitude of these alterations due to high-fat diet was reduced by antioxidant supplementation. Real-time PCR measurements confirmed the changes in transcript levels of cytochrome c oxidase subunit III and superoxide dismutase-1 and -2 noted by microarray approach. Mitochondrial ATP production was unaltered by dietary changes or antioxidant supplementation. It is concluded that the high-fat diet increases the transcription of genes involved in stress response but reduces those of free-radical scavenger enzymes, resulting in reduced DNA repair/metabolism (increased DNA damage). Antioxidants partially prevent these changes. Mitochondrial functions in skeletal muscle remain unaltered by the dietary intervention due to many adaptive changes in gene transcription.