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Omega-3 (ω3) fatty acids are widely investigated for their anti-inflammatory potential, however, there is little evidence regarding their action in the lung parenchyma in the context of obesity. The objective is to investigate the effects of flaxseed oil (FS), rich in α-linolenic (C18:3 - ω3), on the lungs of obese mice. Mice were fed a high-fat diet (HF) for 8 weeks to induce obesity. Subsequently, a part of these animals received HF containing FS oil for another 8 weeks. The HF consumption induced weight gain and hyperglycemia. The lung parenchyma shows a complete fatty acids profile, compared to the control group (CT). In the lung parenchyma, FS increases the ω3 content and, notwithstanding a reduction in the interleukins (IL) IL1β and IL18 contents compared to HF. However, FS promoted increased alveolar spaces, followed by MCP1 (Monocytes Chemoattractant Protein-1) positive cell infiltration and a dramatic reduction in the anti-inflammatory cytokine, IL10. Despite reducing the pulmonary inflammatory response, the consumption of a food source of ω3 was associated with alterations in the lipid profile and histoarchitecture of the lung parenchyma, which can lead to the development of pulmonary complications. This study brings an alert against the indiscriminate use of ω3 supplements, warranting caution., (© 2024 Wiley‐VCH GmbH.)

Senescence impairs liver physiology, mitochondrial function and circadian regulation, resulting in systemic metabolic dysregulation. Given the limited research on the effects of combined exercise on an ageing liver, this study aimed to evaluate its impact on liver metabolism, circadian rhythms and mitochondrial function in senescence-accelerated mouse-prone 8 (SAMP8) and senescence-accelerated mouse-resistant 1 (SAMR1) mice. Histological, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunoblotting analyses were conducted, supplemented by transcriptomic data sets and AML12 hepatocyte studies. Sedentary SAMP8 mice exhibited decreased muscle strength, reduced mitochondrial complex I levels and increased lipid droplet accumulation. In contrast, combined exercise mitigated muscle strength loss, upregulated proteins involved in mitochondrial complexes (CIII, CIV, CV) and increased Bmal1 messenger RNA (mRNA) expression in the liver. These molecular adaptations are associated with healthier liver phenotypes and may influence metabolic function and cellular longevity. Notably, elevated lipid content in aged mice was reduced post-exercise, indicating liver benefits even after a relatively short intervention. The combined exercise regimen did not improve aerobic capacity, likely due to the low volume and brief duration of running. Moreover, no significant effects were observed in SAMR1 mice, possibly because the training intensity was insufficient for younger, healthier animals. These findings underscore the potential of combined strength and endurance exercise to attenuate age-related liver dysfunction, particularly in ageing populations., (© 2024 John Wiley & Sons Australia, Ltd.)

Objectives: The purpose of this study was to examine the relationship between psychological aspects (emotional regulation, self-control, mood states, and perceived stress) and components of run-up variability in horizontal jumps and to conduct comparisons based on sex, events (long jump and triple jump), and contextual situations (training versus competition)., Methods: A total of 10 elite-level athletes (five males and five females) with a mean age of 27.14 (±4.25) years were recruited for the study. All participants had competed nationally or internationally and had 13.10 (±3.48) years of athletic experience. Data were collected during competitions and training sessions for 5 weeks. The participants completed the Brunel Mood Scale, Emotional Regulation Questionnaire, Brief Self-Control Scale, and Visual Analogical Scale of Perceived Stress before each session. The components of run-up variability of successful and failed attempts were measured using video analysis. Data were analyzed using a t-test, Pearson's correlation, and Cohen's d., Results: Athletes specializing in long jump and triple jump displayed similar psychological and run-up variability characteristics. However, females showed higher values for tension and depression, whereas males had higher run-up speeds and vigor. In competitions, athletes tended to have higher vigor, lower fatigue and confusion, an earlier beginning of the adjustment phase, fewer failed attempts, and higher run-up speed than during training. Emotional regulation is inversely related to depression in women during competitions, whereas higher self-control is associated with fewer failed jumps., Conclusion: Athletes competing in the long jump and the triple jump do not differ in psychological traits and run-up characteristics, which suggests that similar training strategies can be used in both events. However, different solutions should be used considering the sex of athletes, with a particular focus on utilizing emotion regulation tools to modulate depression in female jumpers. It is recommended to include training sessions that simulate competition demands, primarily to ensure the early onset of the run-up adjustment phase., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Moura, Moura, Moura, Moura and Brandão.)

Introduction: Obesity presents with structural and functional hypothalamic dysfunction. However, it is unclear whether weight loss can lead to hypothalamic changes. We therefore aimed to conduct a systematic review and meta-analysis to determine the effect of body mass reduction in obese individuals on hypothalamic structure and function., Methods: PubMed, Embase and Cochrane databases were searched for studies that reported the change in hypothalamic structure and function after weight loss. Qualitative and quantitative analyses were performed on magnetic resonance imaging techniques, medio-basal hypothalamus T2-relaxation time, blood oxygen level dependent (BOLD) contrast, voxel-based morphometry (VBM) and biomarkers including glucose, insulin, leptin, ghrelin and inflammatory markers of interleukins. Mean differences between pre- and post-weight loss and 95% confidence intervals (CIs) were pooled using random-effects models., Results: Thirteen pre-post studies were included, of which six accounted for the meta-analysis. Studies showed a favorable decrease in T2-relaxation time ( n  = 1), favorable change in hypothalamic activity after weight loss on BOLD contrast ( n  = 4), with higher peak activities after surgical weight loss ( n  = 2). No differences were found in the gray matter density of the hypothalamus on VBM ( n  = 1). Pooled mean differences between pre- and post-surgical weight loss revealed a decrease of 8.53 mg/dl (95% CI: 5.17, 11.9) in glucose, 7.73 pmol/l (95% CI: 5.07, 10.4) in insulin, 15.5 ng/ml (95% CI: 9.40, 21.6) in leptin, 142.9 pg/ml (95% CI: 79.0, 206.8) in ghrelin and 9.43 pg/ml (95% CI: -6.89, 25.7) in IL-6 level., Conclusions: Our study showed weight reduction in obesity led to limited structural change and significant functional changes in the hypothalamus.

The aim was to understand the direct impact of aerobic short-term exercise on lipid metabolism, specifically in regulating the mitochondrial carrier homolog 2 (MTCH2) and how it interferes with lipid metabolism in mesenteric adipose tissue. Swiss mice were divided into three groups: control, sedentary obese, and exercised obese. The obese groups were induced into obesity for fourteen weeks of a high-fat diet, and the trained submitted to seven aerobic exercise sessions. The exercise proved the significant increase of the pPerilipin-1, a hormone-sensitive lipase gene, and modulates lipid metabolism by increasing the expression of Mtch2 and acetyl Co-A carboxylase, perhaps occurring as feedback to regulate lipid metabolism in adipose tissue. In conclusion, we demonstrate, for the first time, how aerobic physical exercise increases Mtch2 transcription in mesenteric adipose tissue. This increase was due to changes in energy demand caused by exercise, confirmed by observing the significant reduction in mesenteric adipose tissue mass in the exercised group. Also, we showed that physical exercise increased the phosphorylative capacity of PLIN1, a protein responsible for the degradation of fatty acids in the lipid droplet, providing acyl and glycerol for cellular metabolism. Although our findings demonstrate evidence of MTCH2 as a protein that regulates lipid homeostasis, scant knowledge exists concerning the signaling of the MTCH2 pathway in regulatingfatty acid metabolism. Therefore, unveiling the means of molecular signaling of MTCH2 demonstrates excellent potential for treating obesity., Competing Interests: Declaration of competing interest The authors of this study have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Obesity can exacerbate the systemic inflammatory process, leading to increased infiltration of monocytes in white adipose tissue (WAT) and polarization of these cells into pro-inflammatory M1 macrophages, while reducing the population of anti-inflammatory M2 macrophages. Aerobic exercise has been shown to be effective in reducing the pro-inflammatory profile. However, the impact of strength training and the duration of training on macrophage polarization in the WAT of obese individuals have not been widely studied. Therefore, our aim was to investigate the effects of resistance exercise on macrophage infiltration and polarization in the epididymal and subcutaneous adipose tissue of obese mice. We compared the following groups: Control (CT), Obese (OB), Obese 7-day strength training (STO7d), and Obese 15-day strength training (STO15d). Macrophage populations were evaluated by flow cytometry: total macrophages (F4/80+), M1 (CD11c), and M2 (CD206) macrophages. Our results demonstrated that both training protocols improved peripheral insulin sensitivity by increasing AKT phosphorylation (Ser473). Specifically, the 7-day training regimen reduced total macrophage infiltration and M2 macrophage levels without altering M1 levels. In the STO15d group, significant differences were observed in total macrophage levels, M1 macrophages, and the M1/M2 ratio compared to the OB group. In the epididymal tissue, a reduction in the M1/M2 ratio was observed in the STO7d group. Overall, our data demonstrate that 15 days of strength exercise can reduce the M1/M2 ratio of macrophages in white adipose tissue., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

High-fat diet consumption causes hypothalamic inflammation, dysregulating the leptin pathway, which, in turn, compromises the modulation of hypothalamic neuronal activities and predisposes obesity development. Intermittent fasting (IF) and exercise training (ET) have been demonstrated as efficient interventions to modulate hypothalamic inflammation and neuronal activity. However, no studies have evaluated whether combining these interventions could induce better results in reestablishing hypothalamic homeostasis disrupted by high-fat diet intake. The 8-week-old male C57BL/6 mice were randomly assigned into 2 groups: sedentary mice fed a standard diet (CT), and sedentary mice fed a high-fat diet (HF). After 8 weeks of an HF diet, part of the HF group (now 16 weeks old) was randomly subjected to different interventions for 6 weeks: HF-IF = HF diet mice submitted to IF; HF-T = HF diet mice submitted to ET; HF-IFT = HF diet mice submitted to IF and ET. All interventions decreased the body weight gain induced by high-fat diet intake, associated with reduced calorie consumption in week 14. Only the HF-IFT group presented improved serum insulin, leptin, resistin, and Tnf-alpha levels concomitantly with decreased hypothalamic inflammation. The HF-IFT group also demonstrated increased Pomc mRNA expression associated with enhanced pSTAT3 expression in the hypothalamic arcuate and ventromedial hypothalamic nuclei. Our data indicate that the beneficial effects of the combination of IF and ET on energy homeostasis are associated with increased leptin sensitivity in the hypothalamic arcuate nucleus and ventromedial hypothalamic nucleus, which is likely due to an improvement in hypothalamic inflammatory pathways in these nuclei., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The gut has been suggested as the first organ to be affected by unbalanced diets contributing to the obesogenic process. This study aimed to test a short time-course exposition model to a known pro- or anti-inflammatory enriched fatty diet to understand the early gut alterations. Male mice were exposed to the chow diet (CT), high-fat (HF) diet, or a high-fat diet partially replaced on flaxseed oil (FS), rich in omega-3 (ω3), for 14 days. HF and FS increased the total body weight mass compared with the CT group, but FS reduced the epididymal fat depot compared to HF. The bioinformatics from mice and human databases showed the Zo1-Ocln-Cldn7 tight junctions as the main protein-triad. In the ileum, the HF diet has increased IL1β transcript and IL1β, TNFα, and CD11b proteins, but reduced the tight junctions (Zo1, Ocln, and Cld7) compared to the CT group. Despite the FS diet being partially efficient in protecting the ileum against inflammation, the tight junctions were increased, compared to the HF group. The GPR120 and GPR40 receptors were unaffected by diets, but GPR120 was colocalized on the surface of ileum macrophages. The short period of a high-fat diet was enough to start the obesogenic process, ileum inflammation, and reduce the tight junctions. Flaxseed oil did not protect efficiently against dysmetabolism. Still, it increased the tight junctions, even without alteration on inflammatory parameters, suggesting the protection against gut permeability during early obesity development., Competing Interests: Conflict of Interests The authors have declared that no competing interests exist., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Air pollution affects energy homeostasis detrimentally. Yet, knowledge of how each isolated pollutant can impact energy metabolism remains incomplete. The present study was designed to investigate the distinct effects of 1,2-naphthoquinone (1,2-NQ) on energy metabolism since this pollutant increases at the same rate as diesel combustion. In particular, we aimed to determine in vivo effects of subchronic exposure to 1,2-NQ on metabolic and inflammatory parameters of wild-type mice (WT) and to explore the involvement of tumor necrosis factor receptor 1 (TNFR1) and toll-like receptor 4 (TLR4) in this process. Males WT, TNFR1KO, and TLR4KO mice at eight weeks of age received 1,2-NQ or vehicle via nebulization five days a week for 17 weeks. In WT mice, 1,2-NQ slightly decreased the body mass compared to vehicle-WT. This effect was likely due to a mild food intake reduction and increased energy expenditure (EE) observed after six weeks of exposure. After nine weeks of exposure, we observed higher fasting blood glucose and impaired glucose tolerance, whereas insulin sensitivity was slightly improved compared to vehicle-WT. After 17 weeks of 1,2-NQ exposure, WT mice displayed an increased percentage of M1 and a decreased (p = 0.057) percentage of M2 macrophages in adipose tissue. The deletion of TNFR1 and TLR4 abolished most of the metabolic impacts caused by 1,2-NQ exposure, except for the EE and insulin sensitivity, which remained high in these mice under 1,2-NQ exposure. Our study demonstrates for the first time that subchronic exposure to 1,2-NQ affects energy metabolism in vivo. Although 1,2-NQ increased EE and slightly reduced feeding and body mass, the WT mice displayed higher inflammation in adipose tissue and impaired fasting blood glucose and glucose tolerance. Thus, in vivo subchronic exposure to 1,2-NQ is harmful, and TNFR1 and TLR4 are partially involved in these outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)

Objective: Intriguingly, hyperinsulinemia, and hyperglycemia can predispose insulin resistance, obesity, and type 2 diabetes, leading to metabolic disturbances. Conversely, physical exercise stimulates skeletal muscle glucose uptake, improving whole-body glucose homeostasis. Therefore, we investigated the impact of short-term physical activity in a mouse model (Slc2a4 +/- ) that spontaneously develops hyperinsulinemia and hyperglycemia even when fed on a chow diet., Methods: Slc2a4 +/- mice were used, that performed 5 days of endurance or strength exercise training. Further analysis included physiological tests (GTT and ITT), skeletal muscle glucose uptake, skeletal muscle RNA-sequencing, mitochondrial function, and experiments with C2C12 cell line., Results: When Slc2a4 +/- mice were submitted to the endurance or strength training protocol, improvements were observed in the skeletal muscle glucose uptake and glucose metabolism, associated with broad transcriptomic modulation, that was, in part, related to mitochondrial adaptations. The endurance training, but not the strength protocol, was effective in improving skeletal muscle mitochondrial activity and unfolded protein response markers (UPRmt). Moreover, experiments with C2C12 cells indicated that insulin or glucose levels could contribute to these mitochondrial adaptations in skeletal muscle., Conclusions: Both short-term exercise protocols were efficient in whole-body glucose homeostasis and insulin resistance. While endurance exercise plays an important role in transcriptome and mitochondrial activity, strength exercise mostly affects post-translational mechanisms and protein synthesis in skeletal muscle. Thus, the performance of both types of physical exercise proved to be a very effective way to mitigate the impacts of hyperglycemia and hyperinsulinemia in the Slc2a4 +/- mouse model., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Gluten intolerance is associated with several disorders in the body. Although research has grown in recent years, the understanding of its impact on different tissues and the effects of physical exercise in mitigating health problems in the condition of gluten intolerance are still limited. Therefore, our objective was to test whether gliadin would affect metabolism and inflammation in liver tissue and whether aerobic physical exercise would mitigate the negative impacts of gliadin administration in rodents. Wistar rats were divided into exercised gliadin, gliadin, and control groups. Gliadin was administered by gavage from birth to 60 days of age. The rats in the exercised gliadin group performed an aerobic running exercise training protocol for 15 days. At the end of the experiments, physiological, histological, and molecular analyzes were performed in the study. Compared to the control group, the gliadin group had impaired weight gain and increased gluconeogenesis, lipogenesis, and inflammatory biomarkers in the liver. On the other hand, compared to the gliadin group, animals in the exercise-gliadin group had a recovery in body weight, improved insulin sensitivity, and a reduction in some gluconeogenesis, lipogenesis, and inflammatory biomarkers in the liver. In conclusion, our results revealed that the administration of gliadin from birth impaired weight gain and induced an increase in hepatic inflammatory cytokines, which was associated with an impairment of glycemic homeostasis in the liver, all of which were attenuated by adding aerobic exercise training in the gliadin group., (© 2023 Wiley Periodicals LLC.)

It is known that long-term high-fat diet (HF) feeding drastically affects the adipose tissue, contributing to metabolic disorders. Recently, short-term HF consumption was shown to affect different neuronal signaling pathways. Thus, we aimed to evaluate the inflammatory effects of a short-term HF and whether a diet containing omega-3 fatty acid fats from flaxseed oil (FS) has protective effects. Mice were divided into three groups for 3 d, according to their diets: Control group (CT), HF, or FS for 3 d. Lipid profiles were assessed through mass spectrometry and inflammatory markers by RT-qPCR and Western blotting. After short-term HF, mice increased food intake, body weight, adiposity, and fasting glucose. Increased mRNA content of Ccl2 and Tnf was demonstrated in the HF compared to CT in mesenteric adipose tissue. In the liver, TNFα protein was higher in the HF group than in CT, followed by a decreased polyunsaturated fatty acids tissue incorporation in HF. On the other hand, the consumption of FS reduced food intake and fasting glucose, as well as increased omega-3 fatty acid incorporation in MAT and the liver. However, short-term FS was insufficient to control the early inflammation triggered by HF in MAT and the liver. These data demonstrated that a 3-d HF diet is enough to damage glucose homeostasis and trigger inflammation. In contrast, short-term FS protects against increased food intake and fasting glucose but not inflammation in mice., Competing Interests: Declaration of competing interests The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Many conditions, such as inflammation and physical exercise, can induce endoplasmic reticulum (ER) stress. Toll-like Receptor 4 (TLR4) can trigger inflammation and ER stress events. However, there are still no data in the literature regarding the role of TLR4 in ER stress during exercise in skeletal muscle. Therefore, the current investigation aimed to verify the responses of ER stress markers in wild-type (WT) and Tlr4 global knockout (KO) mice after acute and chronic physical exercise protocols. Eight-week-old male WT and KO mice were submitted to acute (moderate or high intensity) and chronic (4-week protocol) treadmill exercises. Under basal conditions, KO mice showed lower performance in the rotarod test. Acute high-intensity exercise increased eIF2α protein in the WT group. After the acute high-intensity exercise, there was an increase in Casp3 and Ddit3 mRNA for the KO mice. Acute moderate exercise increased the cleaved Caspase-3/Caspase-3 in the KO group. In response to chronic exercise, the KO group showed no improvement in any performance evaluation. The 4-week chronic protocol did not generate changes in ATF6, CHOP, p-IRE1α, p-eIF2α/eIF2α, and cleaved Caspase-3/Caspase-3 ratio but reduced BiP protein compared with the KO-Sedentary group. These results demonstrate the global deletion of Tlr4 seems to have the same effects on UPR markers of WT animals after acute and chronic exercise protocols but decreased performance. The cleaved Caspase-3/Caspase-3 ratio may be activated by another pathway other than ER stress in Tlr4 KO animals., (© 2022 John Wiley & Sons Ltd.)

Aging can modify the morphology and function of the liver, such as generating a decrease in the mitochondria content, autophagy, and cell senescence. Although exercise training has several beneficial effects on hepatic metabolism, its actions on autophagy processes, mitochondrial function, and cellular senescence need to be more widely explored. The present study verified the effects of aging and exercise on hepatic circadian markers, autophagy, and mitochondria activity in 24-month-old mice with a combined exercise training protocol. In addition, we used public datasets from human livers in several conditions and BMAL1 knockout mice. C57BL/6 mice were distributed into Control (CT, young, 6-month-old mice), sedentary old (Old Sed, sedentary, 24-month-old mice), and exercised old (Old Ex, 24-month-old mice submitted to a combined exercise training protocol). The exercise training protocol consisted of three days of endurance exercise - treadmill running, and two days of resistance exercise - climbing a ladder, for three weeks. At the end of the protocol, the liver was removed and prepared for histological analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting technique, and oxygen consumption. Heatmaps were built using a human dataset and Bmal1 knockout samples. In summary, the Old Sed had reduced strength, coordination, and balance, as well as a decrease in Bmal1 expression and the presence of degenerated liver cells. Still, this group upregulated the transcription factors related to mitochondrial biogenesis. The Old Ex group had increased strength, coordination, and balance, improved glucose sensitivity, as well as restored Bmal1 expression and the mitochondrial transcription factors. The human datasets indicated that mitochondrial markers and autophagy strongly correlate with specific liver diseases but not aging. We can speculate that mitochondrial and autophagy molecular markers alterations may depend on long-term training., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Dysfunction of the adipose tissue metabolism is considered as a significant hallmark of aging. It has been proposed that α-β hydrolase domain containing 5 (ABHD5) plays a critical role in the control of lipolysis. However, the role of ABHD5 in the control of lipolysis during aging or exercise is unknown. Here we combined the experimental mouse model with transcriptomic analyzes by using murine and human databases to explore the role of ABHD5 in the adipose tissue during aging and in response to exercise. Transcriptomic data revealed a downregulation of Abhd5 messenger RNA levels in the subcutaneous white adipose tissue (scWAT) over time in individuals from 20 to 69 years old. Aged mice displayed dramatic reduction of ABHD5 protein content and lipolytic-related proteins in the scWAT. Interestingly, 4 weeks of high-intensity interval training increased ABHD5 protein level and restored the lipolytic pathway in the scWAT of aged mice. Altogether, our findings demonstrated that aging affects ABHD5 content in the adipose tissue of mice and humans. Conversely, exercise increases ABHD5 activity, recovering the lipolytic activity in aged mice., (© 2022 John Wiley & Sons Ltd.)

The transcriptional repressor REV-ERB-α, encoded by Nuclear Receptor Subfamily 1 Group D Member 1 (Nr1d1), has been considered to play an essential role in the skeletal muscle oxidative capacity adaptation and muscle mass control. Also, this molecule regulates autophagy via the repression of autophagy-related genes both in skeletal muscle and brain regions. Classically, training programs based on endurance or strength characteristics enhance skeletal muscle mass content and/or oxidative capacity, leading to autophagy activation in several tissues. Thus, it seems that REV-ERB-α regulates similar responses induced by exercise. However, how this molecule responds to different exercise models/intensities in different tissues is still unclear. Therefore, the main aim was to characterize the responses of REV-ERB-α and autophagy-related genes to different exercise protocols (endurance/interval run/strength) in distinct tissues (gastrocnemius, soleus and hippocampus). Since REV-ERB-α presents a circadian rhythm, the analyses were performed in a time-course manner. The endurance and strength groups attenuated REV-ERB-α transcriptional response during the time course in gastrocnemius and soleus. Conversely, the interval group enhanced the Nr1d1 expression in the hippocampus. All protocols downregulated the REV-ERB-α protein levels in gastrocnemius following the exercise session with concomitant nuclear exclusion. The major autophagy-related genes presented downregulation after the exercise session in all analyzed tissues. Altogether, these results highlight that REV-ERB-α is extremely sensitive to physical exercise stimuli, including different models and intensities in skeletal muscle and the hippocampus., (© 2022. The Author(s).)

Obesity is a worldwide health problem and is directly associated with insulin resistance and type 2 diabetes. The liver is an important organ for the control of healthy glycemic levels, since insulin resistance in this organ reduces phosphorylation of forkhead box protein 1 (FOXO1) protein, leading to higher hepatic glucose production (HGP) and fasting hyperglycemia. Aerobic physical training is known as an important strategy in increasing the insulin action in the liver by increasing FOXO1 phosphorylation and reducing gluconeogenesis. However, little is known about the effects of strength training in this context. This study aimed to investigate the effects of short-term strength training on hepatic insulin sensitivity and glycogen synthase kinase-3β (GSK3β) and FOXO1 phosphorylation in obese (OB) mice. To achieve this goal, OB Swiss mice performed the strength training protocol (one daily session for 15 days). Short-term strength training increased the phosphorylation of protein kinase B and GSK3β in the liver after insulin stimulus and improved the control of HGP during the pyruvate tolerance test. On the other hand, sedentary OB animals reduced FOXO1 phosphorylation and increased the levels of nuclear FOXO1 in the liver, increasing the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) content. The bioinformatics analysis also showed positive correlations between hepatic FOXO1 levels and gluconeogenic genes, reinforcing our findings. However, strength-trained animals reverted to this scenario, regardless of body adiposity changes. In conclusion, short-term strength training is an efficient strategy to enhance the insulin action in the liver of OB mice, contributing to glycemic control by reducing the activity of hepatic FOXO1 and lowering PEPCK and G6Pase contents., (© 2022 Wiley Periodicals LLC.)

Interleukin 6 (IL-6) acts as a pro and anti-inflammatory cytokine, has an intense correlation with exercise intensity, and activates various pathways such as autophagy and mitochondrial unfolded protein response. Also, IL-6 is interconnected to circadian clock-related inflammation and can be suppressed by the nuclear receptor subfamily 1, group D, member 1 ( Nr1d1 , protein product REV-ERBα). Since IL-6 is linked to physical exercise-modulated metabolic pathways such as autophagy and mitochondrial metabolism, we investigated the relationship of IL-6 with REV-ERBα in the adaptations of these molecular pathways in response to acute intense physical exercise in skeletal muscle. The present study was divided into three experiments. In the first one, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were divided into three groups: Basal time (Basal; sacrificed before the acute exercise), 1 hour (1hr post-Ex; sacrificed 1 hour after the acute exercise), and 3 hours (3hr post-Ex; sacrificed 3 hours after the acute exercise). In the second experiment, C2C12 cells received IL-6 physiological concentrations or REV-ERBα agonist, SR9009. In the last experiment, WT mice received SR9009 injections. After the protocols, the gastrocnemius muscle or the cells were collected for reverse transcription-quantitative polymerase chain reaction (RTq-PCR) and immunoblotting techniques. In summary, the downregulation of REV-ERBα, autophagic flux, and most mitochondrial genes was verified in the IL-6 KO mice independent of exercise. The WT and IL-6 KO treated with SR9009 showed an upregulation of autophagic genes. C2C12 cells receiving IL-6 did not modulate the Nr1d1 mRNA levels but upregulated the expression of some mitochondrial genes. However, when treated with SR9009, IL-6 and mitochondrial gene expression were upregulated in C2C12 cells. The autophagic flux in C2C12 suggest the participation of REV-ERBα protein in the IL-6-induced autophagy. In conclusion, the present study verified that the adaptations required through physical exercise (increases in mitochondrial content and improvement of autophagy machinery) might be intermediated by an interaction between IL-6 and REVERBα., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pinto, Muñoz, da Rocha, Rovina, Ferrari, Alberici, Simabuco, Teixeira, Pauli, de Moura, Cintra, Ropelle, Freitas, Rivas and da Silva.)

Regular endurance exercise is a non-pharmacological strategy to protect the liver against diseases. Conversely, exercise may be harmful when excessive, the so-called overtraining. As expected, mice who underwent an overtraining protocol presented higher levels of proinflammatory cytokines in the serum and liver. Based on the relationship among overtraining, inflammation and mammalian target of rapamycin complex 1 (mTORC1) upregulation, the present study verified if animals submitted to an overtraining protocol, but with inhibition of the mTOR pathway via rapamycin injections could mitigate the liver and serum inflammation. Once autophagy can be linked to the improvement of hepatic dysfunction, we also investigated if the inhibition of mTORC1 by rapamycin can improve hepatic autophagy. The animals were randomized into four groups: control (CT; sedentary mice), overtraining by downhill running (OT; mice submitted to the downhill running-based overtraining protocol), overtraining by downhill running with chronic administration of rapamycin (OT/Rapa; mice submitted to the downhill running-based overtraining protocol with intraperitoneal injections of rapamycin) and aerobic (AER; submitted to aerobic training protocol). The serum and liver of the animals were used for biochemical analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. The main results are (a) OT and OT/Rapa protocols decreased the performance; (b) the protein levels of interleukin 6 (IL-6) were higher for the OT group; the OT/Rapa group reduced the autophagic genes, increased the microtubule-associated protein light chain 3 II/I (LC3II/LC3I) protein ratio and decreased the sequestosome 1 (SQSTM1) protein. In conclusion, rapamycin appears efficiently to increase the autophagy proteins and decrease IL-6 protein in the liver of overtraining mice., (© 2022 John Wiley & Sons Australia, Ltd.)

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation- and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.

The intensity, duration, type of contraction, and muscle damage influence interleukin-6 (IL-6) response to acute exercise. However, in response to an exhaustive exercise session, the upregulation of IL-6 in the serum and heart is associated with an inflammatory condition and can inhibit autophagy. This study aimed to investigate the role of IL-6 in autophagy pathway responses and mitochondrial function in the heart of mice submitted to acute exhaustive physical exercise. The mice were allocated into three groups, five animals per group, for the wild type (WT) and the IL-6 knockout (IL-6 KO): Basal (sedentary; Basal), 1 h (after 1 h of the acute exercise; 1 h), and 3 h (after 3 h of the acute exercise; 3 h). After the specific time for each group, the blood was collected, each mouse heart was removed, and the left ventricle (LV) was isolated. In summary, under basal conditions, without the influence of the acute exercise, the IL-6 KO group showed lower number of nuclei in the cardiac tissue, but higher collagen deposition; lower messenger RNA (mRNA) levels of Prkaa1 and Mtco1, but higher mRNA levels of Ulk1; and higher protein levels of the ratio p-AMPK/AMPK in the heart when compared to WT at the same time point. After the acute exercise (1 and 3 h), the IL-6 KO group had lower mRNA levels of Tfam, Mtnd1, Mtco1, and Nampt in the heart when compared to WT after exercise; higher serum levels of creatine kinase (CK), CK-MB, and lactate dehydrogenase for the IL-6 group when compared to the WT group after the exercise. Specifically, the heat-shock protein 60 protein levels in the heart increased 3 h after exhaustive exercise in the WT group, but not in the IL-6 KO group. The study emphasizes that IL-6 may offer cardioprotective effects, including mitochondrial adaptations in response to acute exhaustive exercise., (© 2022 John Wiley & Sons Ltd.)

The endoplasmic reticulum (ER) is an organelle responsible for the post-translational folding and modification of proteins. Under stress conditions, such as physical exercise, there is accumulation of misfolded proteins. The increased load of proteins in the ER results in ER stress, which activates the unfolded protein response (UPR). UPR is comprised of three parallel pathways, responsible for ensuring the quality of secreted proteins. Scientific studies show that resistance or endurance acute physical exercise can induce ER stress and activate the UPR pathways. On the other hand, regular moderate-intensity exercise can attenuate the responses of genes and proteins related to ER stress. However, these positive adaptations do not occur when exercise intensity and volume increase without adequate rest periods, which is observed in overtraining. The current review discusses the frontier-of-knowledge findings on the effects of different acute and chronic physical exercise protocols on skeletal muscle ER stress and its metabolic consequences., (© 2022 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Obesity is a disease characterized by the exacerbated increase of adipose tissue. A possible way to decrease the harmful effects of excessive adipose tissue is to increase the thermogenesis process, to the greater energy expenditure generated by the increase in heat in the body. In adipose tissue, the thermogenesis process is the result of an increase in mitochondrial work, having as substrate H + ions, and which is related to the increased activity of UCP1. Evidence shows that stress is responsible for increasing the greater induction of UCP1 expression via β-adrenergic receptors. It is known that physical exercise is an important implement for sympathetic stimulation promoting communication between norepinephrine/epinephrine with membrane receptors. Thus, the present study investigates the influence of short-term strength training (STST) on fatty acid composition, lipolysis, lipogenesis, and browning processes in the subcutaneous adipose tissue (sWAT) of obese mice. For this, Swiss mice were divided into three groups: lean control, obesity sedentary, and obese strength training (OBexT). Obese animals were fed a high-fat diet for 14 weeks. Trained obese animals were submitted to 7 days of strength exercise. It was demonstrated that STST sessions were able to reduce fasting glycemia. In the sWAT, the STST was able to decrease the levels of the long-chain fatty acids profile, saturated fatty acid, and palmitic fatty acid (C16:0). Moreover, it was showed that STST did not increase protein levels responsible for lipolysis, the ATGL, ABHD5, pPLIN1, and pHSL. On the other hand, the exercise protocol decreased the expression of the lipogenic enzyme SCD1. Finally, our study demonstrated that the STST increased browning process-related genes such as PGC-1α, PRDM16, and UCP1 in the sWAT. Interestingly, all these biomolecular mechanisms have been observed independently of changes in body weight. Therefore, it is concluded that short-term strength exercise can be an effective strategy to initiate morphological changes in sWAT., (© 2022. The Author(s).)

Intermittent fasting (IF) is a popular intervention used to fight overweight/obesity. This condition is accompanied by hypothalamic inflammation, limiting the proper signaling of molecular pathways, with consequent dysregulation of food intake and energy homeostasis. This mini-review explored the therapeutic modulation potential of IF regarding the disruption of these molecular pathways. IF seems to modulate inflammatory pathways in the brain, which may also be correlated with the brain-microbiota axis, improving hypothalamic signaling of leptin and insulin, and inducing the autophagic pathway in hypothalamic neurons, contributing to weight loss in obesity. Evidence also suggests that when an IF protocol is performed without respecting the circadian cycle, it can lead to dysregulation in the expression of circadian cycle regulatory genes, with potential health damage. In conclusion, IF may have the potential to be an adjuvant treatment to improve the reestablishment of hypothalamic responses in obesity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Oliveira, Morais, Ropelle, de Moura, Cintra, Pauli, de Freitas, Rorato and da Silva.)

Objectives: Based on taurine's beneficial roles in metabolic diseases in rodents and obese individuals, we investigated the effects of taurine supplementation on adipose tissue using transcriptome analysis, 3T3-L1 adipocytes, and subcutaneous white adipose tissue (scWAT) of obese women., Methods: First, we applied bioinformatics analysis to evaluate the effect of the taurine synthesis pathway on the adipose tissue of several BXD mice strains. After that, using 3T3-L1 adipocytes, we investigated the effects of different taurine doses in proteins related to insulin signaling, lipid oxidation, and mitochondrial function. Finally, we evaluated the effects of taurine supplementation (3 grams, 8 wk) on the same proteins in the scWAT of obese women., Results: The transcriptome analysis showed that the taurine biosynthesis pathway was positively associated with insulin signaling and mitochondrial metabolism in the scWAT of BXD mice. The experiments using 3T3-L1 cells highlighted that the taurine dosage has an essential function in taurine synthesis, insulin, and mitochondrial markers. In contrast, the 8-wk taurine administration did not change the basal insulin, proteins of the taurine synthesis or insulin pathways, lipid oxidation, or mitochondrial metabolism in the scWAT of obese women., Conclusions: For the first time, to our knowledge, we showed that supplementation with 3 g of taurine for 8 wk promoted no effect in the insulin signaling pathway in the scWAT of obese women. These findings bring new perspectives to investigate different taurine doses and the intervention period for human studies owing to the potential antiobesity activity of taurine., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The low-grade inflammation is pivotal in obesity and its comorbidities; however, the inflammatory proteins are out of target for traditional drug therapy. Omega-3 (ω3) fatty acids can modulate the downstream signaling of Toll-like receptor (TLR) and tumor necrosis factor-α receptor (TNFα) through GPR120, a G-protein-coupled receptor, a mechanism not yet elucidated in humans. This work aims to investigate if the ω3 supplementation, at a feasible level below the previously recommended level in the literature, is enough to disrupt the inflammation and endoplasmic reticulum stress (ER-stress), and also if in acute treatment (3 h) ω3 can activate the GPR120 in peripheral blood mononuclear cells (PBMC) and leukocytes from overweight non-alcoholic fatty liver disease (NAFLD) participants. The R270H variant of the Ffar4 (GPR120 gene) will also be explored about molecular responses and blood lipid profiles. A triple-blind, prospective clinical trial will be conducted in overweight men and women, aged 19-75 years, randomized into placebo or supplemented (2.2 g of ω3 [EPA+DHA]) groups for 28 days. For sample calculation, it was considered the variation of TNFα protein and a 40% dropout rate, obtaining 22 individuals in each group. Volunteers will be recruited among patients with NAFLD diagnosis. Anthropometric parameters, food intake, physical activity, total serum lipids, complete fatty acid blood profile, and glycemia will be evaluated pre- and post-supplementation. In the PBMC and neutrophils, the protein content and gene expression of markers related to inflammation (TNFα, MCP1, IL1β, IL6, IL10, JNK, and TAK1), ER-stress (ATF1, ATF6, IRE1, XBP1, CHOP, eIF2α, eIF4, HSP), and ω3 pathway (GPR120, β-arrestin2, Tab1/2, and TAK1) will be evaluated using Western blot and RT-qPCR. Participants will be genotyped for the R270H (rs116454156) variant using the TaqMan assay. It is hypothesized that attenuation of inflammation and ER-stress signaling pathways in overweight and NAFLD participants will be achieved through ω3 supplementation through binding to the GPR120 receptor. TRIAL REGISTRATION: ClinicalTrials.gov #RBR-7x8tbx. Registered on May 10, 2018, with the Brazilian Registry of Clinical Trials., (© 2021. The Author(s).)

Hepatic steatosis is directly associated with hepatic inflammation and insulin resistance, which is correlated with hyperglycemia and type 2 diabetes mellitus (T2DM). Aerobic and strength training have been pointed out as efficient strategies against hepatic steatosis. However, little is known about the effects of the combination of those two protocols on hepatic steatosis. Therefore, this study aimed to evaluate the impact of short-term combined training (STCT) on glucose homeostasis and in the synthesis and oxidation of fat in the liver of obesity-induced mice with hepatic steatosis. Swiss mice were distributed into three groups: control lean (CTL), sedentary obese (OB), and combined training obese (CTO). The CTO group performed the STCT protocol, which consisted of strength and aerobic exercises in the same session. The protocol lasted seven days. The CTO group reduced the glucose levels and fatty liver when compared to the OB group. Interestingly, these results were observed even without reductions in body adiposity. CTO group also showed increased hepatic insulin sensitivity, with lower hepatic glucose production (HGP). STCT reduced the expression of the lipogenic genes Fasn and Scd1 and hepatic inflammation, as well as increased the ACC phosphorylation and the oxidative genes Cpt1a and Ppara, reverting the complications caused by obesity. Since this protocol increased lipid oxidation and reduced hepatic lipogenesis, regardless of body fat mass decrease, it can be considered an effective non-pharmacological strategy for the treatment of hepatic steatosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Strategies capable of attenuating TLR4 can attenuate metabolic processes such as inflammation, endoplasmic reticulum (ER) stress, and apoptosis in the body. Physical exercise has been a cornerstone in suppressing inflammation and dysmetabolic outcomes caused by TRL4 activation. Thus, the present study aimed to evaluate the effects of a chronic physical exercise protocol on the TLR4 expression and its repercussion in the inflammation, ER stress, and apoptosis pathways in mice hearts. Echocardiogram, RT-qPCR, immunoblotting, and histological techniques were used to evaluate the left ventricle of wild-type (WT) and Tlr4 knockout (TLR4 KO) mice submitted to a 4-week physical exercise protocol. Moreover, we performed a bioinformatics analysis to expand the relationship of Tlr4 mRNA in the heart with inflammation, ER stress, and apoptosis-related genes of several isogenic strains of BXD mice. The TLR4 KO mice had higher energy expenditure and heart rate in the control state but lower activation of apoptosis and ER stress pathways. The bioinformatics analysis reinforced these data. In the exercised state, the WT mice improved performance and cardiac function. However, these responses were blunted in the KO group. In conclusion, TLR4 has an essential role in the inhibition of apoptosis and ER stress pathways, as well as in the training-induced beneficial adaptations., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Lung cancer is the second leading cause of cancer death worldwide and is strongly associated with cisplatin resistance. The transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer cells and coordinates critical cellular processes as survival, self-renewal, and inflammation. In several types of cancer, STAT3 controls the development, immunogenicity, and malignant behavior of tumor cells while it dictates the responsiveness to radio- and chemotherapy. It is known that STAT3 phosphorylation at Ser727 by mechanistic target of rapamycin (mTOR) is necessary for its maximal activation, but the crosstalk between STAT3 and mTOR signaling in cisplatin resistance remains elusive. In this study, using a proteomic approach, we revealed important targets and signaling pathways altered in cisplatin-resistant A549 lung adenocarcinoma cells. STAT3 had increased expression in a resistance context, which can be associated with a poor prognosis. STAT3 knockout (SKO) resulted in a decreased mesenchymal phenotype in A549 cells, observed by clonogenic potential and by the expression of epithelial-mesenchymal transition markers. Importantly, SKO cells did not acquire the mTOR pathway overactivation induced by cisplatin resistance. Consistently, SKO cells were more responsive to mTOR inhibition by rapamycin and presented impairment of the feedback activation loop in Akt. Therefore, rapamycin was even more potent in inhibiting the clonogenic potential in SKO cells and sensitized to cisplatin treatment. Mechanistically, STAT3 partially coordinated the cisplatin resistance phenotype via the mTOR pathway in non-small cell lung cancer. Thus, our findings reveal important targets and highlight the significance of the crosstalk between STAT3 and mTOR signaling in cisplatin resistance. The synergic inhibition of STAT3 and mTOR potentially unveil a potential mechanism of synthetic lethality to be explored for human lung cancer treatment., (Copyright © 2021. Published by Elsevier Inc.)

Interventions that can modulate subcutaneous white adipose tissue (scWAT) function, such as exercise training and nutritional components, like taurine, modulate the inflammatory process, therefore, may represent strategies for obesity treatment. We investigated the effects of taurine supplementation in conjunction with exercise on inflammatory and oxidative stress markers in plasma and scWAT of obese women. Sixteen obese women were randomized into two groups: Taurine supplementation group (Tau, n = 8) and Taurine supplementation + exercise group (Tau + Exe, n = 8). The intervention was composed of daily taurine supplementation (3 g) and exercise training for 8 weeks. Anthropometry, body fat composition, and markers of inflammatory and oxidative stress were determined in plasma and scWAT biopsy samples before and after the intervention. We found that, although taurine supplementation increased taurine plasma levels, no changes were observed for the anthropometric characteristics. However, Tau alone decreased interleukin-6 (IL-6), and in conjunction with exercise (Tau + Exe), increased anti-inflammatory interleukins (IL-15 and IL10), followed by reduced IL1β gene expression in the scWAT of obese women. Tau and Tau + Exe groups presented reduced adipocyte size and increased connective tissue and multilocular droplets. In conclusion, taurine supplementation in conjunction with exercise modulated levels of inflammatory markers in plasma and scWAT, and improved scWAT plasticity in obese women, promoting protection against obesity-induced inflammation. TRN NCT04279600 retrospectively registered on August 18, 2019., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Obesity is closely related to insulin resistance and type 2 diabetes genesis. The liver is a key organ to glucose homeostasis since insulin resistance in this organ increases hepatic glucose production (HGP) and fasting hyperglycemia. The protein-tyrosine phosphatase 1B (PTP1B) may dephosphorylate the IR and IRS, contributing to insulin resistance in this organ. Aerobic exercise is a great strategy to increase insulin action in the liver by reducing the PTP1B content. In contrast, no study has shown the direct effects of strength training on the hepatic metabolism of PTP1B. Therefore, this study aims to investigate the effects of short-term strength exercise (STSE) on hepatic insulin sensitivity and PTP1B content in obese mice, regardless of body weight change. To achieve this goal, obese Swiss mice were submitted to a strength exercise protocol lasting 15 days. The results showed that STSE increased Akt phosphorylation in the liver and enhanced the control of HGP during the pyruvate tolerance test. Furthermore, sedentary obese animals increased PTP1B content and decreased IRS-1/2 tyrosine phosphorylation; however, STSE was able to reverse this scenario. Therefore, we conclude that STSE is an important strategy to improve the hepatic insulin sensitivity and HGP by reducing the PTP1B content in the liver of obese mice, regardless of changes in body weight.

Lung cancer is the leading cause of cancer‑associated death worldwide and exhibits intrinsic and acquired therapeutic resistance to cisplatin (CIS). The present study investigated the role of mTOR signaling and other signaling pathways after metformin (MET) treatment in control and cisplatin‑resistant A549 cells, mapping pathways and possible targets involved in CIS sensitivity. MTT, flow cytometry, clonogenic assay, western blotting, proteomic analysis using the Stable Isotope Labeling by Amino acids in Cell culture (SILAC) approach and reverse transcription‑quantitative PCR were performed. The results revealed that CIS treatment induced mTOR signaling pathway overactivation, and the mTOR status was restored by MET. MET and the mTOR inhibitor rapamycin (RAPA) decreased the viability in control and resistant cells, and decreased the cell size increase induced by CIS. In control cells, MET and RAPA decreased colony formation after 72 h and decreased IC 50 values, potentiating the effects of CIS. Proteomics analysis revealed important pathways regulated by MET, including transcription, RNA processing and IL‑12‑mediated signaling. In CIS‑resistant cells, MET regulated the apoptotic process, oxidative stress and G 2 /M transition. Annexin 4 (ANXA4) and superoxide dismutase 2 (SOD2), involved in apoptosis and oxidative stress, respectively, were chosen to validate the SILAC analysis and may represent potential therapeutic targets for lung cancer treatment. In conclusion, the chemosensitizing and antiproliferative effects of MET were associated with mTOR signaling and with potential novel targets, such as ANXA4 and SOD2, in human lung cancer cells.

Interleukin-6 (IL-6) is associated with pathological cardiac hypertrophy and can be dramatically increased in serum after an acute strenuous exercise session. However, IL-6 is also associated with the increased production and release of anti-inflammatory cytokines and the inhibition of tumor necrosis factor-alpha (TNF-α) after chronic moderate exercise. To elucidate the relevance of IL-6 in inflammatory and hypertrophic signaling in the heart in response to an acute strenuous exercise session, we combined transcriptome analysis using the BXD mice database and exercised IL-6 knockout mice (IL-6KO). Bioinformatic analysis demonstrated that low or high-levels of Il6 mRNA in the heart did not change the inflammation- and hypertrophy-related genes in BXD mice strains. On the other hand, bioinformatic analysis revealed a strong positive correlation between Il6 gene expression in skeletal muscle with inflammation-related genes in cardiac tissue in several BXD mouse strains, suggesting that skeletal muscle-derived IL-6 could alter the heart's intracellular signals, particularly the inflammatory signaling. As expected, an acute strenuous exercise session increased IL-6 levels in wild-type, but not in IL-6KO mice. Despite not showing morphofunctional differences in the heart at rest, the IL-6KO group presented a reduction in physical performance and attenuated IL-6, TNF-α, and IL-1beta kinetics in serum, as well as lower p38MAPK phosphorylation, Ampkalpha expression, and higher Acta1 and Tnf gene expressions in the left ventricle in the basal condition. In response to strenuous exercise, IL-6 ablation was linked to a reduction in the pro-inflammatory response and higher activation of classical physiological cardiac hypertrophy proteins., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The impairment of mitochondrial metabolism is a hallmark of aging. Mitonuclear imbalance and the mitochondrial unfolded protein response (UPRmt) are two conserved mitochondrial mechanisms that play critical roles in ensuring mitochondrial proteostasis and function. Here, we combined bioinformatics, physiological, and molecular analyses to examine the role of mitonuclear imbalance and UPRmt in the skeletal muscle of aged rodents and humans. The analysis of transcripts from the skeletal muscle of aged humans (60-70 years old) revealed that individuals with higher levels of UPRmt-related genes displayed a consistent increase in several mitochondrial-related genes, including the OXPHOS-associated genes. Interestingly, high-intensity interval training (HIIT) was effective in stimulating the mitonuclear imbalance and UPRmt in the skeletal muscle of aged mice. Furthermore, these results were accompanied by higher levels of several mitochondrial markers and improvements in physiological parameters and physical performance. These data indicate that the maintenance or stimulation of the mitonuclear imbalance and UPRmt in the skeletal muscle could ensure mitochondrial proteostasis during aging, revealing new insights into targeting mitochondrial metabolism by using physical exercise.

Obesity is a chronic, non-transmissible and multifactorial disease commonly associated with systemic inflammation and damage to health. This disorder has been pointed out as leading to the development of a diversity of eye diseases and, consequently, damage to visual acuity. More specifically, cardiometabolic risk is associated with lacrimal gland dysfunctions, since it changes the inflammatory profile favoring the development and worsening of dry eye disease. In more severe and extreme cases, obesity, inflammation, and diabetes mellitus type 2 can trigger the total loss of vision. In this scenario, besides its numerous metabolic functions, clusterin, an apolipoprotein, has been described as protective to the ocular surface through the seal mechanism. Thus, the current review aimed to explain the role of clusterin in dry eye disease that can be triggered by obesity and diabetes.

Purpose: To evaluate the effects of taurine supplementation associated or not with chronic exercise on body composition, mitochondrial function, and expression of genes related to mitochondrial activity and lipid oxidation in the subcutaneous white adipose tissue (scWAT) of obese women., Methods: A randomized and double-blind trial was developed with 24 obese women (BMI 33.1 ± 2.9 kg/m 2 , 32.9 ± 6.3 y) randomized into three groups: Taurine supplementation group (Tau, n = 8); Exercise group (Ex, n = 8); Taurine supplementation + exercise group (TauEx, n = 8). The intervention was composed of 3 g of taurine or placebo supplementation and exercise training for eight weeks. Anthropometry, body fat composition, indirect calorimetry, scWAT biopsy for mitochondrial respiration, and gene expression related to mitochondrial activity and lipid oxidation were assessed before and after the intervention., Results: No changes were observed for the anthropometric characteristics. The Ex group presented an increased resting energy expenditure rate, and the TauEx and Ex groups presented increased lipid oxidation and a decreased respiratory quotient. Both trained groups (TauEx and Ex) demonstrated improved scWAT mitochondrial respiratory capacity. Regarding mitochondrial markers, no changes were observed for the Tau group. The TauEx group had higher expression of CIDEA, PGC1a, PRDM16, UCP1, and UCP2. The genes related to fat oxidation (ACO2 and ACOX1) were increased in the Tau and Ex groups, while only the TauEx group presented increased expression of CPT1, PPARa, PPARγ, LPL, ACO1, ACO2, HSL, ACOX1, and CD36 genes., Conclusion: Taurine supplementation associated with exercise improved lipid metabolism through the modulation of genes related to mitochondrial activity and fatty acid oxidation, suggesting a browning effect in the scWAT of obese women., Competing Interests: Conflicts of interest The authors FGDC, CFCB, GB, AOS, GDF, LCA, VRM, JRP, LPM, ERR, ASRS, MVMJ, JSM, and ECF declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Although physical exercise-induced autophagy activation has been considered a therapeutic target to enhance tissue health and extend lifespan, the effects of different exercise models on autophagy in specific metabolic tissues are not completely understood. This descriptive investigation compared the acute effects of endurance (END), exhaustive (ET), strength (ST), and concurrent (CC) physical exercise protocols on markers of autophagy, genes, and proteins in the gastrocnemius muscle, heart, and liver of mice. The animals were euthanized immediately (0 h) and six hours (6 h) after the acute exercise for the measurement of glycogen levels, mRNA expression of Prkaa1 , Ppargc1a , Mtor , Ulk1 , Becn1 , Atg5 , Map1lc3b , Sqstm1 , and protein levels of Beclin 1 and ATG5. The markers of autophagy were measured by quantifying the protein levels of LC3II and Sqstm1/p62 in response to three consecutive days of intraperitoneal injections of colchicine. In summary, for gastrocnemius muscle samples, the main alterations in mRNA expressions were observed after 6 h and for the ST group, and the markers of autophagy for the CC group were increased (i.e., LC3II and Sqstm1/p62). In the heart, the Beclin 1 and ATG5 levels were downregulated for the ET group. Regarding the markers of autophagy, the Sqstm1/p62 in the heart tissue was upregulated for the END and ST groups, highlighting the beneficial effects of these exercise models. The liver protein levels of ATG5 were downregulated for the ET group. After the colchicine treatment, the liver protein levels of Sqstm1/p62 were decreased for the END and ET groups compared to the CT, ST, and CC groups. These results could be related to diabetes and obesity development or liver dysfunction improvement, demanding further investigations.

The anatomy of the hypothalamus includes many nuclei and a complex network of neurocircuits. In this context, some hypothalamic nuclei reside closer to the blood-brain barrier, allowing communication with the peripheral organs through some molecules, such as leptin. Leptin is considered the main adipokine for energy homeostasis control. Furthermore, leptin signalling in the hypothalamus can communicate with insulin signalling through the activation of phosphoinositide 3-kinase (PI3k). Previous data suggest that isoforms of PI3k are necessary to mediate insulin action in the hypothalamus. However, obese animals show impairment in the central signalling of these hormones. Thus, in the current study, we evaluated the role of acute exercise in the leptin and insulin pathways in the hypothalamus, as well as in food intake control in obese mice. Although acute physical exercise was not able to modulate leptin signalling, this protocol suppressed the increase in the suppressor of cytokine signalling 3 (SOCS3) protein levels. In addition, acute exercise increased the content of PI3k-p110α protein in the hypothalamus. The exercised animals showed a strong tendency to reduction in cumulative food intake. For the first time, our results indicate physical exercise can increase PI3k-p110α protein content in the hypothalamus of obese mice and regulate food intake., (© 2020 Anatomical Society.)

The maintenance of mitochondrial activity in hypothalamic neurons is determinant to the control of energy homeostasis in mammals. Disturbs in the mitochondrial proteostasis can trigger the mitonuclear imbalance and mitochondrial unfolded protein response (UPR mt ) to guarantee the mitochondrial integrity and function. However, the role of mitonuclear imbalance and UPR mt in hypothalamic cells are unclear. Combining the transcriptomic analyses from BXD mice database and in vivo experiments, we demonstrated that physical training alters the mitochondrial proteostasis in the hypothalamus of C57BL/6J mice. This physical training elicited the mitonuclear protein imbalance, increasing the mtCO-1/Atp5a ratio, which was accompanied by high levels of UPR mt markers in the hypothalamus. Also, physical training increased the maximum mitochondrial respiratory capacity in the brain. Interestingly, the transcriptomic analysis across several strains of the isogenic BXD mice revealed that hypothalamic mitochondrial DNA-encoded genes were negatively correlated with body weight and several genes related to the orexigenic response. As expected, physical training reduced body weight and food intake. Interestingly, we found an abundance of mt-CO1, a mitochondrial DNA-encoded protein, in NPY-producing neurons in the lateral hypothalamus nucleus of exercised mice. Collectively, our data demonstrated that physical training altered the mitochondrial proteostasis and induced the mitonuclear protein imbalance and UPR mt in hypothalamic cells.

The nuclear receptor subfamily 1, group D member 1 ( Nr1d1) , plays a role in the skeletal muscle's oxidative capacity, mitochondrial biogenesis, atrophy genes, and muscle fiber size. In light of the effects of physical exercise, the present study investigates the acute response of Nr1d1 and genes related to atrophy and mitochondrial biogenesis on endurance and resistance exercise protocols. In this investigation, we observed, after one bout of endurance exercise, an upregulation of Nr1d1 in soleus muscle, but not in the gastrocnemius, and some genes related to mitochondrial biogenesis and atrophy were enhanced as well. Also, analysis of muscle transcripts from diverse isogenic BXD mice families revealed that the strains with higher Nr1d1 gene expression displayed upregulation of AMPK signaling and mitochondrial-related genes. In summary, a single session of endurance exercise can enhance the Nr1d1 mRNA levels in an oxidative muscle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rovina, da Rocha, Marafon, Pauli, de Moura, Cintra, Ropelle and da Silva.)

The hypothalamus plays a critical role in the control of food consumption and energy expenditure. Fatty diets can elicit an inflammatory response in specific hypothalamic cells, including astrocytes, tanycytes, and microglia, disrupting anorexigenic signals in region-specific hypothalamic neurons, contributing to overeating and body weight gain. In this study, we present an update regarding the knowledge of the effects of physical exercise on inflammatory signaling and circuits to control hunger in the hypothalamus in obesity conditions. To try to understand changes in the hypothalamus, we review the use of magnetic resonance/anorexigenic hormone analysis in humans, as well as in animal models to explore the physiological and molecular mechanism by which exercise modulates satiety signals, such as the central anti-inflammatory response, myokine delivery from skeletal muscle, and others. The accumulation of scientific evidence in recent years allows us to understand that exercise contributes to weight control, and it is managed by mechanisms that go far beyond "burning calories.", (Copyright © 2021 International Society of Exercise and Immunology. All rights reserved.)

Autophagy plays an essential role in body homeostasis achievement. One of the main proteins involved in this process is the LC3I, which, after lipidation, leads to the formation of LC3II that participates in the formation and maturation of autophagosome. This descriptive study verified the responses of LC3II to LC3I proteins, as well as the time-course of this ratio in mice livers after different types of acute physical exercise protocols. Eight-week-old male C57BL/6 mice were maintained three per cage with controlled temperature (22±2 °C) on a 12:12-h light-dark normal cycle with food (Purina chow) and water ad libitum. Mice were randomly divided into four groups: control (CT, sedentary mice), resistance (RE, submitted to a single bout of resistance exercise), endurance (EE, submitted to a single bout of endurance exercise), and concurrent (CE, submitted to a single bout of endurance combined with resistance exercise). The mice livers were extracted and used for the immunoblotting technique. The hepatic LC3B II/I ratio for the RE and EE groups were not altered during the different time-points. For the CE group, there was a decrease in this ratio 12h after exercise compared to time 0 and 18h. Also, the hepatic LC3B II/I ratios were not different among the acute physical exercise protocols along the time-course. The hepatic LC3B II/I ratio was not influenced by the endurance and resistance protocols but decreased in response to the concurrent protocol at 12h after the stimulus.

Cardiovascular diseases are a leading cause of death for adults worldwide. Published articles have shown that toll-like receptor 4 (TLR4), a member of the toll-like receptor (TLR) family, is involved in several cardiovascular diseases and can be modulated by physical exercise. TLR4 is the most expressed TLR in cardiac tissue and is an essential mediator of the inflammatory and apoptosis processes in the heart, playing a pivotal role in the development of cardiovascular diseases. Physical exercise is recognized as a non-pharmacological strategy for the prevention and treatment of these diseases. In addition, physical exercise can modulate the TLR4 in the mice heart, and its absence attenuates apoptosis, endoplasmic reticulum stress, and inflammation. However, the relationship between TLR4 and physical exercise-induced cardiac adaptations has barely been explored. Thus, the objective of this brief review was to discuss studies describing how TLR4 influences cardiac responses to physical exercise and present a link between these responses and cardiovascular diseases, showing physical activity improves the cardiac function of individuals with cardiovascular diseases through the TLR4 modulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The impairment of the mitochondrial functions is a hallmark of aging. During aging, there is a downregulation of two mechanisms strictly associated with mitochondrial integrity, including the mitonuclear imbalance (eg, imbalance in mitochondrial- versus nuclear-encoded mitochondrial proteins) and the mitochondrial unfolded protein response (UPRmt). Here, we evaluated the effects of aerobic exercise in the mitonuclear imbalance and UPRmt markers in the skeletal muscle of old mice. We combined the physiological tests, molecular and bioinformatic analyzes to evaluate the effects of 4 weeks of aerobic exercise training on mitonuclear imbalance and UPRmt markers in the skeletal muscle of young (2 months) and aged (24 months) C57BL/6J mice. Initially, we found that aging reduced several mitochondrial genes in the gastrocnemius muscle, and it was accompanied by the low levels of UPRmt markers, including Yme1l1 and Clpp mRNA. As expected, physical training improved the whole-body metabolism and physical performance of aged mice. The aerobic exercise increased key proteins involved in the mitochondrial biogenesis/functions (VDAC and SIRT1) along with mitochondrial-encoded genes (mtNd1, mtCytB, and mtD-Loop) in the skeletal muscle of old mice. Interestingly, aerobic exercise induced the mitonuclear imbalance, increasing MTCO1/ATP5a ratio and UPRmt markers in the skeletal muscle, including HSP60, Lonp1, and Yme1L1 protein levels in the gastrocnemius muscle of aged mice. These data demonstrate that aerobic exercise training induced mitonuclear imbalance and UPRmt in the skeletal muscle during aging. These phenomena could be involved in the improvement of the mitochondrial metabolism and oxidative capacity in aged individuals., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The protective effects of chronic moderate exercise-mediated autophagy include the prevention and treatment of several diseases and the extension of lifespan. In addition, physical exercise may impair cellular structures, requiring the action of the autophagy mechanism for clearance and renovation of damaged cellular components. For the first time, we investigated the adaptations on basal autophagy flux in vivo in mice's liver, heart, and skeletal muscle tissues submitted to four different chronic exercise models: endurance, resistance, concurrent, and overtraining. Measuring the autophagy flux in vivo is crucial to access the functionality of the autophagy pathway since changes in this pathway can occur in more than five steps. Moreover, the responses of metabolic, performance, and functional parameters, as well as genes and proteins related to the autophagy pathway, were addressed. In summary, the regular exercise models exhibited normal/enhanced adaptations with reduced autophagy-related proteins in all tissues. On the other hand, the overtrained group presented higher expression of Sqstm1 and Bnip3 with negative morphological and physical performance adaptations for the liver and heart, respectively. The groups showed different adaptions in autophagy flux in skeletal muscle, suggesting the activation or inhibition of basal autophagy may not always be related to improvement or impairment of performance.

Obesity is linked to a reduction in the control of hepatic glucose production, which is the primary mechanism related to fasting hyperglycemia and the development of type 2 diabetes mellitus (T2DM). The main system involved in hepatic gluconeogenesis synthesis is controlled by pyruvate carboxylase (PC), which increases in obesity conditions. Recently, we showed that short-term strength training is an important tool against obesity-induced hyperglycemia. As aerobic exercise can reduce the hepatic PC content of obese animals, we hypothesized that strength exercise can also decrease this gluconeogenic enzyme. Therefore, this study investigated whether the metabolic benefits promoted by short-term strength training are related to changes in hepatic PC content. Swiss mice were divided into three groups: lean control (Ctl), obese sedentary (ObS), and obese short-term strength training (STST). The STST protocol was performed through one session/day for 15 days. The obese exercised animals had reduced hyperglycemia and insulin resistance. These results were related to better control of hepatic glucose production and hepatic insulin sensitivity. Our bioinformatics analysis showed that hepatic PC mRNA levels have positive correlations with glucose levels and adiposity, and negative correlations with locomotor activity and muscle mass. We also found that hepatic mRNA levels are related to lipogenic markers in the liver. Finally, we observed that the obese animals had an increased hepatic PC level; however, STST was efficient in reducing its amount. In conclusion, we provide insights into new biomolecular mechanisms by showing how STST is an efficient tool against obesity-related hyperglycemia and T2DM, even without body weight changes.