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.
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.
Based on the crosstalk of inflammation with apoptosis, autophagy, and endoplasmic reticulum (ER) stress, the main objective of this study was to explore the role of interleukin-6 (IL-6) on genes and ...proteins related to these phenomena in the livers of mice submitted to acute exhaustive exercise.
Reverse transcription-quantitative polymerase chain reaction and immunoblotting technique were used to evaluate the livers of wild-type (WT) and IL-6 knockout (KO) mice at baseline (BL) and 3 h after the acute exhaustive physical exercise (EE).
Compared to the WT at baseline, the IL-6 KO had lower exhaustion velocity, mRNA levels of Mtor, Ulk1, Map1lc3b, and Mapk14, and protein contents of ATG5 and p-p70S6K/p70S6K. For the WT group, the EE decreased glycemia, mRNA levels of Casp3, Mtor, Ulk1, Foxo1a, Mapk14, and Ppargc1a, and protein contents of ATG5 and p-p70S6K/p70S6K, but increased mRNA levels of Sqstm1. For the IL-6 KO group, the EE decreased glycemia, mRNA levels of Casp3 and Foxo1a, and protein contents of pAkt/Akt and Mature/Pro IL-1beta, but increased mRNA levels of Sqstm1, and protein contents of p-AMPK/AMPK.
The inhibition of the hepatic autophagy markers induced by the acute EE was attenuated in IL-6 KO mice, highlighting a new function of this cytokine.
•Taurine is associated with insulin signaling and mitochondrial metabolism in mice.•Taurine doses modulated taurine synthesis and AMP-activated protein kinase pathways in 3T3-L1 cells.•A dose of 0.5 ...mM of taurine upregulated insulin pathways in 3T3-L1 cells.•Taurine did not modulate markers of mitochondrial function in subcutaneous white adipose tissue of obese women.•Taurine did not modulate taurine or insulin pathways in subcutaneous white adipose tissue of obese women.
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.
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.
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.
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.
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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.
Ribosomal S6 kinase 1 (S6K1) and S6K2 proteins are effectors of the mammalian target of rapamycin complex 1 pathway, which control the process of protein synthesis in eukaryotes. S6K2 is associated ...with tumor progression and has a conserved C‐terminus polyproline rich motif predicted to be important for S6K2 interactions. It is noteworthy that the translation of proteins containing sequential prolines has been proposed to be dependent of eukaryotic translation initiation factor 5A (eIF5A) translation factor. Therefore, we investigated the importance of polyproline‐rich region of the S6K2 for its intrinsic phosphorylation activity, protein‐protein interaction and eIF5A role in S6K2 translation. In HeLa cell line, replacing S6K2 polyproline by the homologous S6K1‐sequence did not affect its kinase activity and the S6K2 endogenous content was maintained after eIF5A gene silencing, even after near complete depletion of eIF5A protein. Moreover, no changes in S6K2 transcript content was observed, ruling out the possibility of compensatory regulation by increasing the mRNA content. However, in the budding yeast model, we observed that S6K2 production was impaired when compared with S6K2∆Pro, after reduction of eIF5A protein content. These results suggest that although the polyproline region of S6K2 is capable of generating ribosomal stalling, the depletion of eIF5A in HeLa cells seems to be insufficient to cause an expressive decrease in the content of endogenous S6K2. Finally, coimmunoprecipitation assays revealed that the replacement of the polyproline motif of S6K2 alters its interactome and impairs its interaction with RPS6, a key modulator of ribosome activity. These results evidence the importance of S6K2 polyproline motif in the context of S6Ks function.
In this study, we investigated the importance of S6K2 polyproline region for its interactome and dependence of eIF5A for its translation, since the eIF5A has been proposed to act on polyproline motifs. In HeLa cells, the endogenous content of S6K2 was maintained after depletion of eIF5A. However, using yeast as a heterologous expression system, eIF5A depletion negatively affects S6K2 content. These results suggest that although the polyproline region of S6K2 generates ribosomal stalling, the depletion of eIF5A in HeLa cells is insufficient to cause a decrease in the content of endogenous S6K2. We also demonstrated that the replacement of the polyproline motif of S6K2 alters its interactome and impairs its interaction with RPS6.
Characterization of Human Respiratory Syncytial Virus (HRSV) protein interactions with host cell components is crucial to devise antiviral strategies. Viral nucleoprotein, phosphoprotein and matrix ...protein genes were optimized for human codon usage and cloned into expression vectors. HEK-293T cells were transfected with these vectors, viral proteins were immunoprecipitated, and co-immunoprecipitated cellular proteins were identified through mass spectrometry. Cell proteins identified with higher confidence scores were probed in the immunoprecipitation using specific antibodies. The results indicate that nucleoprotein interacts with arginine methyl-transferase, methylosome protein and Hsp70. Phosphoprotein interacts with Hsp70 and tropomysin, and matrix with tropomysin and nucleophosmin. Additionally, we performed immunoprecipitation of these cellular proteins in cells infected with HRSV, followed by detection of co-immunoprecipitated viral proteins. The results indicate that these interactions also occur in the context of viral infection, and their potential contribution for a HRSV replication model is discussed.
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.
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