Moderate-Intensity Combined Training Induces Lipidomic Changes in Individuals with Obesity and Type 2 Diabetes.

CONTEXT: Alterations in the lipid metabolism are linked to metabolic disorders such as insulin resistance (IR), obesity and type 2 diabetes (T2D). Regular exercise, particularly combined training (CT), is a well-known non-pharmacological treatment that combines aerobic (AT) and resistance (RT) training benefits. However, it is unclear whether moderate-intensity exercise without dietary intervention induces changes in lipid metabolism to promote a 'healthy lipidome'. OBJECTIVE: The study aimed to investigate the effect of 16 weeks of CT on plasma and white adipose tissue in both sexes, middle-aged subjects with normal weight, obesity and T2D using an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) untargeted lipidomics approach. METHODS: Body composition, maximum oxygen consumption (VO2 max), strength, and biochemical markers were evaluated before and after the control/training period and correlated with lipid changes. CT consisted of 8 to 10 RT exercises, followed by 35 min of AT (45 -70% VO2 max), 3 times a week for 16 weeks. RESULTS: The CT significantly reduced the levels of saturated and monounsaturated fatty acid side-chains (SFA/MUFA) in sphingolipids, glycerolipids (GL) and glycerophospholipids (GP) as well as reducing fat mass, circumferences and IR. Increased levels of polyunsaturated fatty acids in GPs, and GLs were also observed, along with increased fat-free mass, VO2 max, and strength (all p < 0.05) after training. CONCLUSION: Our study stated that 16 weeks of moderate-intensity CT remodelled the lipid metabolism in OB, and T2D individuals, even without dietary intervention, establishing a link between exercise-modulated lipid markers and mechanisms that reduce IR and obesity-related comorbidities.

Rho-Kinase Is Differentially Expressed in the Adipose Tissue of Rodent and Human in Response to Aging, Sex, and Acute Exercise.

White adipose tissue (WAT) controls energy storage, expenditure, and endocrine function. Rho-kinase (ROCK) is related to impaired thermogenesis, downregulation of preadipocyte differentiation, and adipokine production. Furthermore, WAT ROCK responds to metabolic stress from high-fat diets or diabetes. However, ROCK distribution in adipose depots and its response to aging and sex remain unclear. Thus, we aim to investigate ROCK function in adipose tissue of rodent and human in response to aging and sex. We observed specific differences in the ROCK1/2 distribution in inguinal WAT (ingWAT), perigonadal WAT (pgWAT), and brown adipose tissue of male and female rodents. However, ROCK2 expression was lower in female ingWAT compared with males, a fact that was not observed in the other depots. In the pgWAT and ingWAT of male and female rodents, ROCK activity increased during development. Moreover, middle-aged female rodents and humans showed downregulation in ROCK activity after acute physical exercise. Interestingly, ROCK levels were associated with several inflammatory markers both in rats and humans WAT (Nfkb1, Tnf, Il1b, Il6, and Mcp1). Induction of cell senescence by etoposide elevates ROCK activity in human preadipocytes; however, silencing ROCK1/2 demonstrates improvement in the inflammatory and cell senescence state. Using public databases, several pathways were strongly associated with ROCK modulation in WAT. In summary, WAT ROCK increases with development in association with inflammatory markers. Further, ROCK activity was attenuated by acute physical exercise, implicating it as a possible therapeutic target for metabolism improvement mediated by adipose tissue inflammatory state changes.

Effects of Different Exercise Types on Chrna7 and Chrfam7a Expression in Healthy Normal Weight and Overweight Type 2 Diabetic Adults.

Purpose: Considering that the CHRNA7 and CHRFAM7A genes can be modulated by acute or chronic inflammation, and exercise modulates inflammatory responses, the question that arises is whether physical exercise could exert any effect on the expression of these genes. Thus, the aim of this work is to identify the effects of different types of exercises on the expression of the CHRNA7, CHRFAM7A and tumor necrosis factor-α (TNF-α) in leukocytes of healthy normal weight (HNW), and overweight with type 2 diabetes (OT2D) individuals. Methods: 15 OT2D and 13 HNW participants (men and women, from 40 to 60 years old) performed in a randomized crossover design three exercise sessions: aerobic exercise (AE), resistance exercise (RE) and combined exercise (CE). Blood samples were collected at rest and post-60-min of the exercise sessions. The leukocytes were the analysis of the CHRNA7, CHRFAM7A and (TNF-α) gene expression. Results: At baseline, OT2D had higher CHRFAM7A and TNF-α expression compared to HNW. No statistical differences were observed between groups for CHRNA7; however, the HNW group presented almost twice as many subjects with the expression of this gene (24% vs. 49%). Post exercise, the CHRFAM7A increased in AE, RE and CE for HNW, and in AE and CE for OT2D. There was no significant difference for TNF-α and CHRNA7 expression between any type of exercise and group. Conclusions: Our study shows that OT2D individuals presented higher baseline expression of TNF-α and CHRFAM7A, besides evidence of decreased CHRNA7A expression in leukocytes when compared with HNW. On the other hand, acutely physical exercise induces increased CHRFAM7A expression, especially when the aerobic component is present.

Combined training increases thermogenic fat activity in patients with overweight and type 2 diabetes.

BACKGROUND: Exercise is an important strategy in the management of diabetes. Experimental studies have shown that exercise acts, at least in part, by inducing the production of myokines that improve metabolic control and activate brown/beige adipose tissue depots. Combined training (CT) is recommended by the major diabetes guidelines due to its metabolic and cardiovascular benefits, however, its impact on brown/beige adipose tissue activities has never been tested in humans with overweight and type 2 diabetes (T2D). Here, we evaluated the effects of 16-week combined training (CT) program on brown adipose tissue activity; browning and autophagy markers, and serum pro-thermogenic/inflammatory inducers in patients with overweight and T2D. METHODS: Thirty-four patients with overweight and T2D were assigned to either a control group (CG) or a combined training group (CTG) in a randomized and controlled study. Functional/fitness parameters, anthropometry/body composition parameters, blood hormone/biochemical parameters, thermogenic/autophagic gene expression in subcutaneous adipose tissue were evaluated before and at the end of the intervention. In addition, cold-induced 18-Fluoroxyglucose Positron Emission Computed Tomography (18F-FDG PET/CT) was performed in the training group before and after the end of the intervention. RESULTS: CT increased cervical/supraclavicular brown adipose tissue (BAT) thermogenic activity (p = 0.03) as well as in perirenal adipose tissue (p = 0.02). In addition, CT increased the expression of genes related to thermogenic profile (TMEM26: + 95%, p = 0.04; and EPSTI1: + 26%, p = 0.03) and decreased autophagic genes (ULK1: -15%, p = 0.04; LC3: -5%, p = 0.02; and ATG4: -22%, p < 0.001) in subcutaneous adipose tissue. There were positive correlations between Δ% BAT activity with Δ% of post training energy expenditure cold exposure, HDL-c, IL4, adiponectin, irisin, meteorin-like, and TMEM26 and ZIC1 genes, besides negative correlations with LDL-c, total cholesterol and C-reactive protein. CONCLUSION: This is the first evidence of the beneficial actions of CT on adipose tissue thermogenic activity in humans, and it adds important support for the recommendation of CT as a strategy in the management of diabetes.

Acute/Chronic Responses of Combined Training on Serum Pro-thermogenic/Anti-inflammatory Inducers and Its Relation With Fed and Fasting State in Overweight Type 2 Diabetic Individuals.

Concentrations of pro-thermogenic/anti-inflammatory inductors are influenced by fed/fasting, sedentary/trained states, and metabolic pattern. However, there is a lack of information on the interactions of these conditions, especially in humans. Thus, the present study aimed to evaluate the chronic and acute training responses as well as the fed/fasted states of serum pro-thermogenic/anti-inflammatory inducers in overweight type 2 diabetics individuals. Fifteen individuals with type 2 diabetes [body mass index (BMI): 29.61 ± 3.60 kg/m2; age: 50.67 ± 3.97 years] participated in the study. In the pre- and post-experimental periods, baseline clinical parameters analyses were performed. Pro-thermogenic/anti-inflammatory inductors were evaluated pre/post-baseline and before, shortly after, and after 30' and 60' in the first and last sessions of a 16-week combined training (CT) period. These inducers were also compared for fasting and feeding before and after the training period. CT has improved baseline physical fitness, metabolic pattern, and it has also increased interleukin (IL)33 and FNDC5/irisin. In the first training session, there was a decrease in IL4, IL13, and IL33, besides an increase in FNDC5/irisin, and natriuretic peptides. In the last training session, there was an increase in natriuretic peptides and bone morphogenic protein 4 (BMP4). Differences in responses between the first and last training sessions were observed at certain post-session times for IL4, IL33, and natriuretic peptides, always with higher concentrations occurring in the last session. In evaluating the area under the curve (AUC) of the first and last training session, FNDC5/irisin, natriuretics peptides, and meteorin-like showed increased areas in the last training session. The pre-training fed state showed an increase in IL4 and IL33, while in fasting there was an increase in meteorin-like, natriuretic peptides, and FNDC5/irisin. In the post-training, IL4, IL13, and IL33 were increased in the fed state, while meteorin-like, natriuretic peptides, and FNDC5/irisin remained increased in the fast. Adaptation to physical training and a better metabolic pattern favor an improvement in the acute secretory pattern in part of pro-thermogenic and anti-inflammatory substances analyzed. The fed and fasting states also interfere differently in these substances, where fasting interferes with the increase of myokines, while the fed state induces an increase in interleukins. Clinical Trial Registration: [http://www.ensaiosclinicos.gov.br/rg/RBR-62n5qn/], identifier [U1111-1202-1476].

Association of skeletal muscle and serum metabolites with maximum power output gains in response to continuous endurance or high-intensity interval training programs: The TIMES study - A randomized controlled trial.

BACKGROUND: Recent studies have begun to identify the molecular determinants of inter-individual variability of cardiorespiratory fitness (CRF) in response to exercise training programs. However, we still have an incomplete picture of the molecular mechanisms underlying trainability in response to exercise training. OBJECTIVE: We investigated baseline serum and skeletal muscle metabolomics profile and its associations with maximal power output (MPO) gains in response to 8-week of continuous endurance training (ET) and high-intensity interval training (HIIT) programs matched for total units of exercise performed (the TIMES study). METHODS: Eighty healthy sedentary young adult males were randomized to one of three groups and 70 were defined as completers (> 90% of sessions): ET (n = 30), HIIT (n = 30) and control (CO, n = 10). For the CO, participants were asked to not exercise for 8 weeks. Serum and skeletal muscle samples were analyzed by 1H-NMR spectroscopy. The targeted screens yielded 43 serum and 70 muscle reproducible metabolites (intraclass > 0.75; coefficient of variation < 25%). Associations of baseline metabolites with MPO trainability were explored within each training program via three analytical strategies: (1) correlations with gains in MPO; (2) differences between high and low responders to ET and HIIT; and (3) metabolites contributions to the most significant pathways related to gains in MPO. The significance level was set at P < 0.01 or false discovery rate of 0.1. RESULTS: The exercise programs generated similar gains in MPO (ET = 21.4 ± 8.0%; HIIT = 24.3 ± 8.5%). MPO associated baseline metabolites supported by all three levels of evidence were: serum glycerol, muscle alanine, proline, threonine, creatinine, AMP and pyruvate for ET, and serum lysine, phenylalanine, creatine, and muscle glycolate for HIIT. The most common pathways suggested by the metabolite profiles were aminoacyl-tRNA biosynthesis, and carbohydrate and amino acid metabolism. CONCLUSION: We suggest that MPO gains in both programs are potentially associated with metabolites indicative of baseline amino acid and translation processes with additional evidence for carbohydrate metabolism in ET.

Obese with higher FNDC5/Irisin levels have a better metabolic profile, lower lipopolysaccharide levels and type 2 diabetes risk

ABSTRACT Objective: Thus, the aim of this study was to compare if higher or smaller fibronectin type 3 domain-containing protein 5 (FNDC5)/irisin levels are associated with inflammatory and metabolic markers, caloric/macronutrient intake, physical fitness and type 2 diabetes mellitus (T2DM) risk in obese middle-aged men, and also to correlate all variables analyzed with FNDC5/irisin. Subjects and methods: On the basis of a cluster study, middle-aged obese men (IMC: 31.01 ± 1.64 kg/m2) were divided into groups of higher and smaller levels of FNDC5/irisin. The levels of leptin, resistin, adiponectin, tumor necrosis factor alpha (TNFα), interleukin 6 and 10 (IL6, IL10), lipopolysaccharide (LPS), glucose, insulin, glycated hemoglobin, insulin resistance and sensibility, lipid profile, risk of T2DM development, body composition, rest energy expenditure, caloric/macronutrient intake and physical fitness were measured. Results: The higher FNDC5/ irisin group presented improved insulin sensibility (homeostasis model assessment - sensibility (HOMA-S) (p = 0.01) and QUICKI index (p < 0.01)), insulin (p = 0.02) and triglyceride levels (p = 0.01), lower insulin resistance (homeostasis model assessment - insulin resistance (HOMA-IR) (p = 0.01), triglycerides/glucose (TYG index) (p = 0.02), neck circumference (p = 0.02), risk of T2DM development (p = 0.02), tendency to decrease serum resistin (p = 0.08) and significant lower LPS levels (p = 0.02). Inverse correlations between FNDC5/irisin and body weight (r −0.46, p = 0.04), neck circumference (r −0.51, p = 0.02), free fat mass (r −0.49, p = 0.02), triglycerides (r −0.43, p = 0.05) and risk of developing T2DM (r −0.61, p = 0.04) were observed. Conclusions: These results suggest that higher FNDC5/irisin levels in obese middle-aged men are related to a better metabolic profile and lower risk of T2DM development and serum LPS, a potential inducer of insulin resistance.

Combined training, FNDC5/irisin levels and metabolic markers in obese men: A randomised controlled trial.

The effects of training on FNDC5/irisin and its association with fitness and metabolic marker improvements induced by training have been poorly investigated in humans. Thus, the present study assessed the effects of combined training (CT) on FNDC5/irisin levels, metabolic markers and fitness adaptations in obese men. Middle-age obese men (age 49.13 ± 5.75, body mass index (BMI) 30.86 ± 1.63) were randomly distributed in the CT group (n = 12) and control group (CG n = 10). The CT consisted of strength followed by aerobic training, 3 times/week, for 24 weeks. Body composition, physical fitness, plasma FNDC5/irisin, biochemical markers and metabolic scores/index were evaluated. CT maintained FNDC5/irisin levels (µg/mL) (pre: 4.15 ± 0.32, post: 4.21 ± 0.32; p = .96) and improved body composition, metabolic and physical fitness markers. In the CG, decreased FNDC5/irisin (µg/mL) (pre: 4.36 ± 0.23, post: 3.57 ± 0.94; p = .01) and reduced strength (supine exercise/kg) (pre: 71 ± 14.7, post: 60.1 ± 14.05; p < .01) were observed, along with a trend to increase HOMA-IR (pre: 2.63 ± 1.11, post: 3.14 ± 1.27; p = .07) and other indicators of metabolic deterioration. An inverse correlation was found between the change (Δ%) in levels of FNDC5/irisin and Δ% glucose, Δ% total cholesterol, Δ% triglycerides and Δ% waist circumference, in addition to a positive relation with Δ% muscle strength. In conclusion, CT maintained FNDC5/irisin levels and provided metabolic and fitness benefits. The correlation between FNDC5/irisin changes and metabolic parameters, as well as the FNDC5/irisin reduction associated with fitness and metabolic worsening in the CG, suggests a relationship between FNDC5/irisin and a healthy metabolic status in humans.

Obese with higher FNDC5/Irisin levels have a better metabolic profile, lower lipopolysaccharide levels and type 2 diabetes risk.

OBJECTIVE: Thus, the aim of this study was to compare if higher or smaller fibronectin type 3 domain-containing protein 5 (FNDC5)/irisin levels are associated with inflammatory and metabolic markers, caloric/macronutrient intake, physical fitness and type 2 diabetes mellitus (T2DM) risk in obese middle-aged men, and also to correlate all variables analyzed with FNDC5/irisin. SUBJECTS AND METHODS: On the basis of a cluster study, middle-aged obese men (IMC: 31.01 ± 1.64 kg/m2) were divided into groups of higher and smaller levels of FNDC5/irisin. The levels of leptin, resistin, adiponectin, tumor necrosis factor alpha (TNFα), interleukin 6 and 10 (IL6, IL10), lipopolysaccharide (LPS), glucose, insulin, glycated hemoglobin, insulin resistance and sensibility, lipid profile, risk of T2DM development, body composition, rest energy expenditure, caloric/macronutrient intake and physical fitness were measured. RESULTS: The higher FNDC5/ irisin group presented improved insulin sensibility (homeostasis model assessment - sensibility (HOMA-S) (p = 0.01) and QUICKI index (p < 0.01)), insulin (p = 0.02) and triglyceride levels (p = 0.01), lower insulin resistance (homeostasis model assessment - insulin resistance (HOMA-IR) (p = 0.01), triglycerides/glucose (TYG index) (p = 0.02), neck circumference (p = 0.02), risk of T2DM development (p = 0.02), tendency to decrease serum resistin (p = 0.08) and significant lower LPS levels (p = 0.02). Inverse correlations between FNDC5/irisin and body weight (r -0.46, p = 0.04), neck circumference (r -0.51, p = 0.02), free fat mass (r -0.49, p = 0.02), triglycerides (r -0.43, p = 0.05) and risk of developing T2DM (r -0.61, p = 0.04) were observed. CONCLUSIONS: These results suggest that higher FNDC5/irisin levels in obese middle-aged men are related to a better metabolic profile and lower risk of T2DM development and serum LPS, a potential inducer of insulin resistance.

Metabolomics and Exercise: possibilities and perspectives

Abstract Aim This review aimed to provide an overview of the publications using metabolomics in research with physical exercises and to demonstrate how researchers have been applying this approach. Methods A systematic search in the databases Web of Science, SCOPUS and PubMed was performed, with the key words: "metabolomics" OR "metabonomics" and with "metabolomics" OR "metabonomics" AND "exercise" in the title or abstract of the articles. The search period was from 2000 to 2016. Forty-four original articles were selected. The studies found were separated into four categories: metabolic responses to physical exercise, supplementation and physical exercise, sports performance, and physical exercise related to diseases. Results It was possible to observe the exponential growth of the use of this approach in Sports and Health Sciences, and the four sub-fields towards which these researches involving exercise are directed, enabling a more comprehensive characterization of different metabolic profiles, as well as their study for identifying new biomarkers related to physical exercise. Conclusions The possibilities of using metabolomics approach are increasing in the fields of Health Sciences, Sports, and Physical Activity. The experimental design of the study is essential to take advantage of this tool and be able to answer questions in the metabolism comprehension.(AU)