Folate induces stemness and increases oxygen consumption under glucose deprivation by notch-1 pathway activation in colorectal cancer cell.

Evidence for folate's protective effects on neural tube defects led the USA and Chile to start mandatory folic acid (FA) fortification programs, decreasing up to 50%. However, ∼30% of the population consuming fortified foods reach supraphysiologic serum levels. Although controversial, several epidemiological and clinical observations suggest that folate increases cancer risk, giving concern about the risks of FA supplementation. The Cancer stem cells (CSCs) model has been used to explain survival to anticancer therapies. The Notch-1 pathway plays a role in several cancers and is associated with the stemness process. Different studies show that modulation of metabolic pathways regulates stemness capacity in cancer. Supraphysiologic concentrations of FA increase the proliferation of HT-29 cells by Notch-1 activation. However, whether folate can induce a stemness-like phenotype in cancer is not known. We hypothesized that FA protects from glucose deprivation-induced cell death through Notch-1 activation. HT-29 cells were challenged with glucose deprivation at basal (20 nM) and supraphysiological (400 nM) FA and 5-MTHF concentrations. We analyzed changes in stemness-like gene expression, cell death and different energetic metabolic functions. Supraphysiological concentrations of FA increased stemness-like genes, and improved survival and oxygen consumption, inducing AMPK phosphorylation and HSP-70 protein expression. We evaluated the Notch-1 pathway using the DAPT and siRNA as inhibitors, decreasing the stemness-like gene expression and preventing the FA protection against glucose deprivation-induced cell death. Moreover, they decreased oxygen consumption and AMPK phosphorylation. These results suggest that FA protects against glucose deprivation. These effects were associated with AMPK activation, a critical metabolic mediator in nutrient consumption and availability that activates the Notch-1 pathway.

Mitofusin-2 induced by exercise modifies lipid droplet-mitochondria communication, promoting fatty acid oxidation in male mice with NAFLD.

BACKGROUND AND AIM: The excessive accumulation of lipid droplets (LDs) is a defining characteristic of nonalcoholic fatty liver disease (NAFLD). The interaction between LDs and mitochondria is functionally important for lipid metabolism homeostasis. Exercise improves NAFLD, but it is not known if it has an effect on hepatic LD-mitochondria interactions. Here, we investigated the influence of exercise on LD-mitochondria interactions and its significance in the context of NAFLD. APPROACH AND RESULTS: Mice were fed high-fat diet (HFD) or HFD-0.1 % methionine and choline-deficient diet (MCD) to emulate simple hepatic steatosis or non-alcoholic steatohepatitis, respectively. In both models, aerobic exercise decreased the size of LDs bound to mitochondria and the number of LD-mitochondria contacts. Analysis showed that the effects of exercise on HOMA-IR and liver triglyceride levels were independent of changes in body weight, and a positive correlation was observed between the number of LD-mitochondria contacts and NAFLD severity and with the lipid droplet size bound to mitochondria. Cellular fractionation studies revealed that ATP-coupled respiration and fatty acid oxidation (FAO) were greater in hepatic peridroplet mitochondria (PDM) from HFD-fed exercised mice than from equivalent sedentary mice. Finally, exercise increased FAO and mitofusin-2 abundance exclusively in PDM through a mechanism involving the curvature of mitochondrial membranes and the abundance of saturated lipids. Accordingly, hepatic mitofusin-2 ablation prevented exercise-induced FAO in PDM. CONCLUSIONS: This study demonstrates that aerobic exercise has beneficial effects in murine NAFLD models by lessening the interactions between hepatic LDs and mitochondria, and by decreasing LD size, correlating with a reduced severity of NAFLD. Additionally, aerobic exercise increases FAO in PDM and this process is reliant on Mfn-2 enrichment, which modifies LD-mitochondria communication.

High-intensity interval training prevents muscle mass loss in overweight Chilean young adults during a hypocaloric-Mediterranean diet: a randomized trial.

The hypocaloric Mediterranean diet (MD) mainly reduces fat mass but inevitably causes a loss of skeletal muscle mass. High-intensity interval training (HIIT) seems to have advantages in preserving muscle mass during a hypocaloric regime. Our study compares body composition and metabolic changes in overweight and obese Chilean women and men after 3 months of weight loss treatment with a Mediterranean-type hypocaloric diet, HIIT, or a combination of both. The study included 83 overweight or obese women and men between the ages of 25 and 50. The subjects were randomly assigned to one of the three intervention groups: (1) MD, (2) EX, and (3) MD + EX. Baseline and post-intervention measurements included: (a) body composition by dual-beam densitometry, muscle, and fat measurements by thigh ultrasound and computed tomography; (b) handgrip and quadriceps muscle strength; (c) exercise performance by peak oxygen consumption, peak load, work efficiency, and exercise energy expenditure; and (d) metabolic parameters. Out of 83 participants, the retention rate was 49% due to low compliance with the interventions. As expected, the MD group resulted in significantly greater weight loss (MD -7%, EX -0.6% and MD + EX -5.3%) and appendicular fat mass loss (MD -11.1%, EX -2.9, MD + EX -10.2%) but was associated with significant lean tissue loss (2.8%), which was prevented by HIIT (EX -0.1 and MD + EX -0.6%). Metabolic and glycoxidative parameters remained unchanged, irrespective of changes in body composition. Hypocaloric diets remain the most effective means to lose weight and body fat. However, it induces a loss of lean body mass when not accompanied by exercise training. This study shows that HIIT prevents the loss of muscle mass caused by a hypocaloric Mediterranean diet.

Methods for studying primary cilia in heart tissue after ischemia-reperfusion injury.

Cardiovascular diseases are the leading cause of death and disability worldwide. After heart injury triggered by myocardial ischemia or myocardial infarction, extensive zones of tissue are damaged and some of the tissue dies by necrosis and/or apoptosis. The loss of contractile mass activates a series of biochemical mechanisms that allow, through cardiac remodeling, the replacement of the dysfunctional heart tissue by fibrotic material. Our previous studies have shown that primary cilia, non-motile antenna-like structures at the cell surface required for the activation of specific signaling pathways, are present in cardiac fibroblasts and required for cardiac fibrosis induced by ischemia/reperfusion (I/R) in mice. I/R-induced myocardial fibrosis promotes the enrichment of ciliated cardiac fibroblasts where the myocardial injury occurs. Given discussions about the existence of cilia in specific cardiac cell types, as well as the functional relevance of studying cilia-dependent signaling in cardiac fibrosis after I/R, here we describe our methods to evaluate the presence and roles of primary cilia in cardiac fibrosis after I/R in mice.

Exercise Induces an Augmented Skeletal Muscle Mitochondrial Unfolded Protein Response in a Mouse Model of Obesity Produced by a High-Fat Diet.

Increase in body fat contributes to loss of function and changes in skeletal muscle, accelerating sarcopenia, a phenomenon known as sarco-obesity or sarcopenic obesity. Studies suggest that obesity decreases the skeletal muscle (SM)'s ability to oxidize glucose, increases fatty acid oxidation and reactive oxygen species production, due to mitochondrial dysfunction. Exercise improves mitochondrial dysfunction in obesity; however, it is not known if exercise regulates the mitochondrial unfolded protein response (UPRmt) in the SM. Our study aimed to determine the mito-nuclear UPRmt in response to exercise in a model of obesity, and how this response is associated with the improvement in SM functioning after exercise training. C57BL/6 mice were fed a normal diet and high-fat diet (HFD) for 12 weeks. After 8 weeks, animals were subdivided into sedentary and exercised for the remaining 4 weeks. Grip strength and maximal velocity of mice submitted to HFD improved after training. Our results show an increase in the activation of UPRmt after exercise while in obese mice, proteostasis is basally decreased but shows a more pronounced increase with exercise. These results correlate with improvement in the circulating triglycerides, suggesting mitochondrial proteostasis could be protective and could be related to mitochondrial fuel utilization in SM.

The CB1 cannabinoid receptor regulates autophagy in the tibialis anterior skeletal muscle in mice.

The endocannabinoid system (ECS) regulates energy metabolism, has been implicated in the pathogenesis of metabolic diseases and exerts its actions mainly through the type 1 cannabinoid receptor (CB1). Likewise, autophagy is involved in several cellular processes. It is required for the normal development of muscle mass and metabolism, and its deregulation is associated with diseases. It is known that the CB1 regulates signaling pathways that control autophagy, however, it is currently unknown whether the ECS could regulate autophagy in the skeletal muscle of obese mice. This study aimed to investigate the role of the CB1 in regulating autophagy in skeletal muscle. We found concomitant deregulation in the ECS and autophagy markers in high-fat diet-induced obesity. In obese CB1-KO mice, the autophagy-associated protein LC3 II does not accumulate when mTOR and AMPK phosphorylation levels do not change. Acute inhibition of the CB1 with JD-5037 decreased LC3 II protein accumulation and autophagic flux. Our results suggest that the CB1 regulates autophagy in the tibialis anterior skeletal muscle in both lean and obese mice.

The CB1 cannabinoid receptor regulates autophagy in the tibialis anterior skeletal muscle in mice

The endocannabinoid system (ECS) regulates energy metabolism, has been implicated in the pathogenesis of metabolic diseases and exerts its actions mainly through the type 1 cannabinoid receptor (CB1). Likewise, autophagy is involved in several cellular processes. It is required for the normal development of muscle mass and metabolism, and its deregulation is associated with diseases. It is known that the CB1 regulates signaling pathways that control autophagy, however, it is currently unknown whether the ECS could regulate autophagy in the skeletal muscle of obese mice. This study aimed to investigate the role of the CB1 in regulating autophagy in skeletal muscle. We found concomitant deregulation in the ECS and autophagy markers in high-fat diet-induced obesity. In obese CB1-KO mice, the autophagy-associated protein LC3 II does not accumulate when mTOR and AMPK phosphorylation levels do not change. Acute inhibition of the CB1 with JD-5037 decreased LC3 II protein accumulation and autophagic flux. Our results suggest that the CB1 regulates autophagy in the tibialis anterior skeletal muscle in both lean and obese mice.

Effect of Structured Phenolic Lipids with EPA/DHA and Gallic Acid against Metabolic-Associated Fatty Liver Disease (MAFLD) in Mice.

Obesity is the leading risk factor for developing metabolic (dysfunction)-associated fatty liver disease (MAFLD). The food industry has an essential role in searching for new strategies to improve primary food sources to revert some of the metabolic alterations induced by obesity. There is consistent evidence that long-chain polyunsaturated fatty acids (n-3 LCPUFA) belonging to the n-3 series, i.e., eicosapentaenoic (20:5n-3, EPA) and docosahexaenoic (22:6n-3, DHA) acids, could revert some alterations associated with obesity-induced metabolic diseases. A relevant tool is the synthesis of structured acylglycerols (sAG), which include EPA or DHA at the sn-2 position. On the other hand, it has been reported that a crucial role of antioxidants is the reversion of MAFLD. In this work, we studied the effects of new molecules incorporating gallic acid (GA) into EPA/DHA-rich structured lipids. Mice were fed with a high-fat diet (60%) for three months and were then divided into five groups for supplementation with sAG and sAG structured with gallic acid (structured phenolic acylglycerols, sPAG). sPAG synthesis was optimized using a 2²-screening factorial design based on the response surface methodology (RSM). Our results show that treatment of sPAG was effective in decreasing visceral fat, fasting glycemia, fasting insulin, suggesting that this new molecule has a potential use in the reversal of MAFLD-associated alterations.

Sucralose consumption ameliorates high-fat diet-induced glucose intolerance and liver weight gain in mice.

Sucralose is one of the most widely used artificial sweeteners used by the food industry to reduce the calorie density of their products. Although broadly regarded as innocuous, studies show contrasting results depending on whether the research subjects are lean or overweight. In this study, we studied the effect of sucralose consumption on glucose homeostasis in a model of obesity. Male C57BL/6J mice were fed ad libitum with control or a high-fat diet (HFD) and drank either water or sucralose (0.1 mg/mL) for 8 weeks. To characterize the ensuing metabolic changes, we evaluated weight gain, glucose and pyruvate tolerance, and physical performance. Also, we assessed markers of steatosis and mitochondrial mass and function in the liver. Our results show that sucralose reduced weight gain, glucose, and pyruvate intolerance, and prevented the decrease in physical performance of HFD-fed mice. In the liver, sucralose also had a positive effect, preventing the decrease in mitochondrial mass exerted by HFD. Altogether, our results indicate that in the context of an obesogenic diet, sucralose has a beneficial effect at the organismal and hepatic levels.

Palmitic acid control of ciliogenesis modulates insulin signaling in hypothalamic neurons through an autophagy-dependent mechanism.

Palmitic acid (PA) is significantly increased in the hypothalamus of mice, when fed chronically with a high-fat diet (HFD). PA impairs insulin signaling in hypothalamic neurons, by a mechanism dependent on autophagy, a process of lysosomal-mediated degradation of cytoplasmic material. In addition, previous work shows a crosstalk between autophagy and the primary cilium (hereafter cilium), an antenna-like structure on the cell surface that acts as a signaling platform for the cell. Ciliopathies, human diseases characterized by cilia dysfunction, manifest, type 2 diabetes, among other features, suggesting a role of the cilium in insulin signaling. Cilium depletion in hypothalamic pro-opiomelanocortin (POMC) neurons triggers obesity and insulin resistance in mice, the same phenotype as mice deficient in autophagy in POMC neurons. Here we investigated the effect of chronic consumption of HFD on cilia; and our results indicate that chronic feeding with HFD reduces the percentage of cilia in hypothalamic POMC neurons. This effect may be due to an increased amount of PA, as treatment with this saturated fatty acid in vitro reduces the percentage of ciliated cells and cilia length in hypothalamic neurons. Importantly, the same effect of cilia depletion was obtained following chemical and genetic inhibition of autophagy, indicating autophagy is required for ciliogenesis. We further demonstrate a role for the cilium in insulin sensitivity, as cilium loss in hypothalamic neuronal cells disrupts insulin signaling and insulin-dependent glucose uptake, an effect that correlates with the ciliary localization of the insulin receptor (IR). Consistently, increased percentage of ciliated hypothalamic neuronal cells promotes insulin signaling, even when cells are exposed to PA. Altogether, our results indicate that, in hypothalamic neurons, impairment of autophagy, either by PA exposure, chemical or genetic manipulation, cause cilia loss that impairs insulin sensitivity.

Formulación de preguntas clínicas estructuradas / Formulation of structured clinical questions

La rehabilitación clínica nos enfrenta constantemente a situaciones de dudas que pueden ser resueltas a través de la practica basada en evidencia. En esta guía metodológica aprenderemos sobre cómo formular este primer importante elemento. De este modo, se podrá consultar a la literatura científica disponible a través de una pregunta clínica estructurada que permita buscar, con la mayor eficiencia posible, las publicaciones relacionadas para responder la pregunta clínica realizada, evaluar y aplicar los resultados encontrados y finalmente valorar su impacto. La pregunta clínica se organiza en el formato PICoR (paciente, intervención, comparación y resultados) para identificar sus componentes y estructurar la búsqueda sistemática de información científica. También tiene utilidad en la metodología de estudios clínicos, define el diseño de la investigación y forma parte importante de la construcción de guías de práctica clínica.

Clinical rehabilitation constantly confronts us with situations of doubt that can be resolved through evidence-based practice. In this methodological guide, we are going to learn about how formulate this first relevant issue. Thereby, it could be possible consulting the available scientific literature through a structured clinical question that allows search for, with the greatest possible efficiency, related publications to answer the clinical question asked, evaluate, and apply the results found, to finally assess their impact. The clinical question is organized in the PICO format (patient, intervention, comparison, and outcome) to identify its components and structure the systematic search for scientific information. It is also useful in the methodology of clinical studies, defines the research design and forms an important part of the construction of clinical practice guidelines.

Hydrogen sulfide disrupts insulin-induced glucose uptake in L6 skeletal muscle cells.

Hydrogen sulfide (H2S) has been known for its toxicity. However, recent studies have focused on the mechanisms involved in endogenous production and function. To date, the H2S role in insulin signaling and glucose homeostasis is unclear. This uncertainty is even more evident in skeletal muscle, a physiological niche highly relevant for regulating glycemia in response to insulin. This study aimed to investigate the role of H2S on insulin signaling and glucose uptake in the L6 skeletal muscle cell line. We evaluated the endogenous synthesis with the fluorescent dye, 7-azido-4-methyl coumarin (7-AzMC). Glucose restriction-induced an increase in the endogenous levels of H2S, likely through stimulation of cystathionine γ-lyase activity, as its specific inhibitor, PAG (5 mM) prevented this increase, and mRNA levels of CSE decreased with glucose and amino acid restriction. Exogenous H2S reduced insulin-induced glucose uptake at 0.5 up to 24 h, an effect dissociated from the level of Akt phosphorylation. Our results show that glucose restriction induces endogenous production of H2S via CSE. In addition, H2S disrupts insulin-induced glucose uptake independent of the Akt pathway. These results suggest that H2S antagonism over insulin-induced glucose uptake could help maintain the plasmatic glucose levels in conditions that provoke hypoglycemia, which could serve as an H2S-regulated mechanism for maintaining glucose plasmatic levels through the inhibition of the skeletal muscle insulin-depended glucose uptake.

Glucocorticoid Receptor ß Overexpression Has Agonist-Independent Insulin-Mimetic Effects on HepG2 Glucose Metabolism.

Glucocorticoids (GC) are steroids hormones that drive circulating glucose availability through gluconeogenesis in the liver. However, alternative splicing of the GR mRNA produces two isoforms, termed GRα and GRß. GRα is the classic receptor that binds to GCs and mediates the most described actions of GCs. GRß does not bind GCs and acts as a dominant-negative inhibitor of GRα. Moreover, GRß has intrinsic and GRα-independent transcriptional activity. To date, it remains unknown if GRß modulates glucose handling in hepatocytes. Therefore, the study aims to characterize the impact of GRß overexpression on glucose uptake and storage using an in vitro hepatocyte model. Here we show that GRß overexpression inhibits the induction of gluconeogenic genes by dexamethasone. Moreover, GRß activates the Akt pathway, increases glucose transports mRNA, increasing glucose uptake and glycogen storage as an insulin-mimetic. Our results suggest that GRß has agonist-independent insulin-mimetic actions in HepG2 cells.

Exercise regulation of hepatic lipid droplet metabolism.

Lipid droplets (LD) are not just lipid stores. They are now recognized as highly dynamic organelles, having a life cycle that includes biogenesis, growth, steady-state, transport, and catabolism. Importantly, LD exhibit different features in terms of size, number, lipid composition, proteins, and interaction with other organelles, and all these features exert an impact on cellular homeostasis. The imbalance of LD function causes non-alcoholic fatty liver disease (NAFLD). Studies show that exercise attenuates NAFLD by decreasing LD content; however, reports show metabolic benefits without changes in LD amount (intrahepatic triglyceride levels) in NAFLD. Due to the multiple effects of exercise in LD features, we think that these metabolic benefits occur through changes in LD features in NAFLD, rather than only the reduction in content. Exercise increases energy mobilization and utilization from storages such as LD, and is one of the non-pharmacological treatments against NAFLD. Therefore, exercise modification of LD could be a target for NAFLD treatment. Here, we review the most up-to-date literature on this topic, and focus on recent findings showing that LD features could play an important role in the severity of NAFLD.

Differential Effects of Oleic and Palmitic Acids on Lipid Droplet-Mitochondria Interaction in the Hepatic Cell Line HepG2.

Fatty acid overload, either of the saturated palmitic acid (PA) or the unsaturated oleic acid (OA), causes triglyceride accumulation into specialized organelles termed lipid droplets (LD). However, only PA overload leads to liver damage mediated by mitochondrial dysfunction. Whether these divergent outcomes stem from differential effects of PA and OA on LD and mitochondria joint dynamics remains to be uncovered. Here, we contrast how both fatty acids impact the morphology and interaction between both organelles and mitochondrial bioenergetics in HepG2 cells. Using confocal microscopy, we showed that short-term (2-24 h) OA overload promotes more and bigger LD accumulation than PA. Oxygen polarography indicated that both treatments stimulated mitochondrial respiration; however, OA favored an overall build-up of the mitochondrial potential, and PA evoked mitochondrial fragmentation, concomitant with an ATP-oriented metabolism. Even though PA-induced a lesser increase in LD-mitochondria proximity than OA, those LD associated with highly active mitochondria suggest that they interact mainly to fuel fatty acid oxidation and ATP synthesis (that is, metabolically "active" LD). On the contrary, OA overload seemingly stimulated LD-mitochondria interaction mainly for LD growth (thus metabolically "passive" LDs). In sum, these differences point out that OA readily accumulates in LD, likely reducing their toxicity, while PA preferably stimulates mitochondrial oxidative metabolism, which may contribute to liver damage progression.

Anthocyanins from Aristotelia chilensis Prevent Olanzapine-Induced Hepatic-Lipid Accumulation but Not Insulin Resistance in Skeletal Muscle Cells.

Type 2 diabetes and obesity are major problems worldwide and dietary polyphenols have shown efficacy to ameliorate signs of these diseases. Anthocyanins from berries display potent antioxidants and protect against weight gain and insulin resistance in different models of diet-induced metabolic syndrome. Olanzapine is known to induce an accelerated form of metabolic syndrome. Due to the aforementioned, we evaluated whether delphinidin-3,5-O-diglucoside (DG) and delphinidin-3-O-sambubioside-5-O-glucoside (DS), two potent antidiabetic anthocyanins isolated from Aristotelia chilensis fruit, could prevent olanzapine-induced steatosis and insulin resistance in liver and skeletal muscle cells, respectively. HepG2 liver cells and L6 skeletal muscle cells were co-incubated with DG 50 µg/mL or DS 50 µg/mL plus olanzapine 50 µg/mL. Lipid accumulation was determined in HepG2 cells while the expression of p-Akt as a key regulator of the insulin-activated signaling pathways, mitochondrial function, and glucose uptake was assessed in L6 cells. DS and DG prevented olanzapine-induced lipid accumulation in liver cells. However, insulin signaling impairment induced by olanzapine in L6 cells was not rescued by DS and DG. Thus, anthocyanins modulate lipid metabolism, which is a relevant factor in hepatic tissue, but do not significantly influence skeletal muscle, where a potent antioxidant effect of olanzapine was found.

Soluble Interleukin-6 Receptor Regulates Interleukin-6-Dependent Vascular Remodeling in Long-Distance Runners.

Little is known about the effects of training load on exercise-induced plasma increase of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) and their relationship with vascular remodeling. We sought to evaluate the role of sIL 6R as a regulator of IL-6-induced vascular remodeling. Forty-four male marathon runners were recruited and allocated into two groups: low-training (LT, <100 km/week) and high-training (HT, ≥100 km/week), 22 athletes per group. Twenty-one sedentary participants were used as reference. IL-6, sIL-6R and sgp130 levels were measured in plasma samples obtained before and immediately after finishing a marathon (42.2-km). Aortic diameter was measured by echocardiography. The inhibitory effect of sIL-6R on IL-6-induced VSMC migration was assessed using cultured A7r5 VSMCs. Basal plasma IL-6 and sIL-6R levels were similar among sedentary and athlete groups. Plasma IL-6 and sIL-6R levels were elevated after the marathon, and HT athletes had higher post-race plasma sIL-6R, but not IL-6, level than LT athletes. No changes in sgp130 plasma levels were found in LT and HT groups before and after running the marathon. Athletes had a more dilated ascending aorta and aortic root than sedentary participants with no differences between HT and LT athletes. However, a positive correlation between ascending aorta diameter and plasma IL-6 levels corrected by training load and years of training was observed. IL-6 could be responsible for aorta dilation because IL-6 stimulated VSMC migration in vitro, an effect that is inhibited by sIL-6R. However, IL-6 did not modify cell proliferation, collagen type I and contractile protein of VSMC. Our results suggest that exercise induces vascular remodeling. A possible association with IL-6 is proposed. Because sIL-6R inhibits IL-6-induced VSMC migration, a possible mechanism to regulate IL-6-dependent VSMC migration is also proposed.

Role of Interleukin-6 in Vascular Health and Disease.

IL-6 is usually described as a pleiotropic cytokine produced in response to tissue injury or infection. As a pro-inflammatory cytokine, IL-6 activates innate and adaptative immune responses. IL-6 is released in the innate immune response by leukocytes as well as stromal cells upon pattern recognition receptor activation. IL-6 then recruits immune cells and triggers B and T cell response. Dysregulated IL-6 activity is associated with pathologies involving chronic inflammation and autoimmunity, including atherosclerosis. However, IL-6 is also produced and released under beneficial conditions, such as exercise, where IL-6 is associated with the anti-inflammatory and metabolic effects coupled with physical adaptation to intense training. Exercise-associated IL-6 acts on adipose tissue to induce lipogenesis and on arteries to induce adaptative vascular remodeling. These divergent actions could be explained by complex signaling networks. Classical IL-6 signaling involves a membrane-bound IL-6 receptor and glycoprotein 130 (gp130), while trans-signaling relies on a soluble version of IL-6R (sIL-6R) and membrane-bound gp130. Trans-signaling, but not the classical pathway, is regulated by soluble gp130. In this review, we discuss the similarities and differences in IL-6 cytokine and myokine signaling to explain the differential and opposite effects of this protein during inflammation and exercise, with a special focus on the vascular system.

Moderate Aerobic Exercise Training Prevents the Augmented Hepatic Glucocorticoid Response Induced by High-Fat Diet in Mice.

Glucocorticoids (GCs) are critical regulators of energy balance. Their deregulation is associated with the development of obesity and metabolic syndrome. However, it is not understood if obesity alters the tissue glucocorticoid receptor (GR) response, and moreover whether a moderate aerobic exercise prevents the alteration in GR response induced by obesity. METHODS: To evaluate the GR response in obese mice, we fed C57BL6J mice with a high-fat diet (HFD) for 12 weeks. Before mice were sacrificed, we injected them with dexamethasone. To assess the exercise role in GR response, we fed mice an HFD and subjected them to moderate aerobic exercise three times a week. RESULTS: We found that mice fed a high-fat diet for 12 weeks developed hepatic GC hypersensitivity without changes in the gastrocnemius or epididymal fat GR response. Therefore, moderate aerobic exercise improved glucose tolerance, increased the corticosterone plasma levels, and prevented hepatic GR hypersensitivity with an increase in epididymal fat GR response. CONCLUSION: Collectively, our results suggest that mice with HFD-induced obesity develop hepatic GR sensitivity, which could enhance the metabolic effects of HFD in the liver. Moreover, exercise was found to be a feasible non-pharmacological strategy to prevent the deregulation of GR response in obesity.