Impact of Breaking up of Sitting Time on Anti-inflammatory Response Induced by Extracellular Vesicles.

Physical inactivity and sedentary behaviors (SB) have promoted a dramatic increase in the incidence of a host of chronic disorders over the last century. The breaking up of sitting time (i.e., sitting to standing up transition) has been proposed as a promising solution in several epidemiological and clinical studies. In parallel to the large interest it initially created, there is a growing body of evidence indicating that breaking up prolonged sedentary time (i.e., > 7 h in sitting time) could reduce overall mortality risks by normalizing the inflammatory profile and cardiometabolic functions. Recent advances suggest that the latter health benefits, may be mediated through the immunomodulatory properties of extracellular vesicles. Primarily composed of miRNA, lipids, mRNA and proteins, these vesicles would influence metabolism and immune system functions by promoting M1 to M2 macrophage polarization (i.e., from a pro-inflammatory to anti-inflammatory phenotype) and improving endothelial function. The outcomes of interrupting prolonged sitting time may be attributed to molecular mechanisms induced by circulating angiogenic cells. Functionally, circulating angiogenic cells contribute to repair and remodel the vasculature. This effect is proposed to be mediated through the secretion of paracrine factors. The present review article intends to clarify the beneficial contributions of breaking up sitting time on extracellular vesicles formation and macrophage polarization (M1 and M2 phenotypes). Hence, it will highlight key mechanistic information regarding how breaking up sitting time protocols improves endothelial health by promoting antioxidant and anti-inflammatory responses in human organs and tissues.

Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects.

OBJECTIVE: To determine whether the metabolic benefits of hypoabsorptive surgeries are associated with changes in the gut endocannabinoidome (eCBome) and microbiome. METHODS: Biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) were performed in diet-induced obese (DIO) male Wistar rats. Control groups fed a high-fat diet (HF) included sham-operated (SHAM HF) and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). Body weight, fat mass gain, fecal energy loss, HOMA-IR, and gut-secreted hormone levels were measured. The levels of eCBome lipid mediators and prostaglandins were quantified in different intestinal segments by LC-MS/MS, while expression levels of genes encoding eCBome metabolic enzymes and receptors were determined by RT-qPCR. Metataxonomic (16S rRNA) analysis was performed on residual distal jejunum, proximal jejunum, and ileum contents. RESULTS: BPD-DS and SADI-S reduced fat gain and HOMA-IR, while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels in HF-fed rats. Both surgeries induced potent limb-dependent alterations in eCBome mediators and in gut microbial ecology. In response to BPD-DS and SADI-S, changes in gut microbiota were significantly correlated with those of eCBome mediators. Principal component analyses revealed connections between PYY, N-oleoylethanolamine (OEA), N-linoleoylethanolamine (LEA), Clostridium, and Enterobacteriaceae_g_2 in the proximal and distal jejunum and in the ileum. CONCLUSIONS: BPD-DS and SADI-S caused limb-dependent changes in the gut eCBome and microbiome. The present results indicate that these variables could significantly influence the beneficial metabolic outcome of hypoabsorptive bariatric surgeries.

Consistent gut bacterial and short-chain fatty acid signatures in hypoabsorptive bariatric surgeries correlate with metabolic benefits in rats.

OBJECTIVE: The study aimed at comparing how changes in the gut microbiota are associated to the beneficial effects of the most clinically efficient hypoabsorptive bariatric procedures, namely Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S). METHODS: Diet-induced obese (DIO) male Wistar rats were divided into seven groups. In addition to the groups subjected to RYGB, BPD-DS and SADI-S, the following four control groups were included: SHAM-operated rats fed a high-fat diet (SHAM HF), SHAM fed a low-fat diet (SHAM LF), SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW) and sleeve-gastrectomy (SG) rats. Body weight, food intake, glucose tolerance, insulin sensitivity/resistance, and L-cell secretion were assessed. The gut microbiota (16 S ribosomal RNA gene sequencing) as well as the fecal and cæcal contents of short-chain fatty acids (SCFAs) were also analyzed prior to, and after the surgeries. RESULTS: The present study demonstrates the beneficial effect of RYGB, BPD-DS and SADI-S on fat mass gain and glucose metabolism in DIO rats. These benefits were proportional to the effect of the surgeries on food digestibility (BPD-DS > SADI-S > RYGB). Notably, hypoabsorptive surgeries led to consonant microbial signatures characterized by decreased abundance of the Ruminococcaceae (Oscillospira and Ruminococcus), Oscillospiraceae (Oscillibacter) and Christensenellaceae, and increased abundance of the Clostridiaceae (Clostridium), Sutterellaceae (Sutterella) and Enterobacteriaceae. The gut bacteria following hypoabsorptive surgeries were associated with higher fecal levels of propionate, butyrate, isobutyrate and isovalerate. Increases in the fecal SCFAs were in turn positively and strongly correlated with the levels of peptide tyrosine-tyrosine (PYY) and with the beneficial effects of the surgery. CONCLUSION: The present study emphasizes the consistency with which the three major hypoabsorptive bariatric procedures RYGB, BPD-DS and SADI-S create a gut microbial environment capable of producing a SCFA profile favorable to the secretion of PYY and to beneficial metabolic effects.

Early administration of L-arginine in mdx neonatal mice delays the onset of muscular dystrophy in tibialis anterior (TA) muscle.

Duchenne muscular dystrophy (DMD) is a genetic disorder that results in the absence of dystrophin, a cytoskeletal protein. Individuals with this disease experience progressive muscle destruction, which leads to muscle weakness. Studies have been conducted to find solutions for the relief of individuals with this disease, several of which have shown that utrophin, a protein closely related to dystrophin, when overexpressed in mdx neonatal mice (the murine model of DMD), is able to prevent the progressive muscle destruction observed in the absence of dystrophin. Furthermore, recent studies have shown that L-arginine induces utrophin upregulation in adult mdx mice. We hypothesized that L-arginine treatment also induces utrophin upregulation to prevent the development of muscle weakness in neonatal mdx mice. Hence, L-arginine should also prevent progressive muscle destruction via utrophin upregulation in mdx neonatal mice. Mdx neonatal mice were injected intraperitoneally daily with 800 mg/kg of L-arginine for 6 weeks, whereas control mice were injected with a physiological saline. The following experiments were performed on the tibialis anterior (TA) muscle: muscle contractility and resistance to mechanical stress; central nucleation and peripheral nucleation, utrophin, and creatine kinase quantification as well as a nitric oxide (NO) assay. Our findings show that early administration of L-arginine in mdx neonatal mice prevents the destruction of the tibialis anterior (TA) muscle. However, this improvement was related to nitric oxide (NO) production rather than the expected utrophin upregulation.

Two weeks of western diet disrupts liver molecular markers of cholesterol metabolism in rats.

BACKGROUND: The present study was designed to test the hypothesis that in the liver, excessive fat accumulation impairs cholesterol metabolism mainly by altering the low-density lipoprotein-receptor (LDL-R) pathway. METHOD: Young male Wistar rats were fed standard (SD), high fat (HFD; 60% kcal) or Western (WD; 40% fat + 35% sucrose (17.5% fructose)) diets for 2 or 6 weeks. RESULTS: Weight gain (~ 40 g) was observed only following 6 weeks of the obesogenic diets (P < 0.01). Compared to the 2-week treatment, obesogenic diets tripled fat pad weight (~ 20 vs 7 g) after 6 weeks. Hepatic triglyceride (TG) levels were greater in response to both the WD and HFD compared to the SD (P < 0.01) at 2 and 6 weeks and their concentrations were greater (P < 0.05) in WD than HFD at 2 weeks. Plasma total cholesterol levels were higher (P < 0.05) in animals submitted to WD. After 2 and 6 weeks, liver expression of LDL-R, proprotein convertase subtilisin/kexin 9 (PCSKk9) and sterol regulatory element binding protein 2 (SREBP2), involved in LDL-cholesterol uptake, was lower in animals submitted to WD than in others treated with HFD or SD (P < 0.01). Similarly, low-density lipoprotein-receptor-related protein 1 (LRP1) and acyl-CoA cholesterol acyltransferase-2 (ACAT-2) mRNA levels were lower (P < 0.01) among WD compared to SD-fed rats. Expression of the gene coding the main regulator of endogenous cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) was reduced in response to WD compared to SD and HFD at 2 (P < 0.001) and 6 (P < 0.05) weeks. Being enriched in fructose, the WD strongly promoted the expression of carbohydrate-response element binding protein (ChREBP) and acetyl-CoA carboxylase (ACC), two key regulators of de novo lipogenesis. CONCLUSION: These results show that the WD promptly increased TG levels in the liver by potentiating fat storage. This impaired the pathway of hepatic cholesterol uptake via the LDL-R axis, promoting a rapid increase in plasma total cholesterol levels. These results indicate that liver fat content is a factor involved in the regulation of plasma cholesterol.

Interplay Between Gut Microbiota and Gastrointestinal Peptides: Potential Outcomes on the Regulation of Glucose Control.

A host of gastrointestinal (GI) peptides influence the regulation of vital functions, such as growth, appetite, stress, gut motility, energy expenditure, digestion and inflammation, as well as glucose and lipid homeostasis. Hence, impairments in the synthesis/secretion of glucagon-like peptide-1 (GLP-1), leptin, nesfatin-1, glucose-dependent insulinotropic peptide (GIP), ghrelin (acylated and unacylated forms), oxyntomodulin, vasoactive intestinal peptide, somatostatin, cholecystokinin, peptide tyrosine‒tyrosine, GLP-2 and pancreatic polypeptide were previously associated with the development of obesity-related disorders. It is currently emphasized that the beneficial metabolic outcomes associated with the normalization of the gut microbiota (GM) is influenced by increases in GLP-1 and peptide YY secretion as well as by decreases in acylated ghrelin production. These effects are associated with reductions in body weight and adiposity in combination with the normalization of glucose and lipid metabolism. However, important questions remain unanswered regarding how GLP-1, peptide tyrosine‒tyrosine, acylated ghrelin and other metabolically relevant GI peptides interact with the GM to modulate the host's metabolic functions. In addition, it is likely that the GM and other biologically active GI peptides influence metabolic functions, such as glucose control, although the mechanisms remain ill-defined. In this review, we investigate how GM and GI peptides influence glucose metabolism in experimental models, such as germ-free animals and dietary interventions. Emphasis is placed on pathways through which GM and GI peptides could modulate intestinal permeability, nutrient absorption, short-chain fatty acid production, metabolic endotoxemia, oxidative stress and low-grade inflammation.

Timing of high-intensity intermittent exercise affects ad libitum energy intake in overweight inactive men.

The present study sought to clarify the impact of exercise intensity and timing on energy intake and appetite-related blood variables. Fourteen inactive overweight men were included in the study. Firstly, maximal aerobic power (MAP) was measured. Then, participants randomly performed 5 experimental sessions consisting of 30 min of steady-state exercise (SSE) at 50% of MAP, high-intensity intermittent exercise (HIIE) with 30s repetitions at MAP and 30s of passive recovery or no exercise (CTRL). Sessions were performed 1h (SSE1h and HIIE1h) or 2.5h (SSE2.5h and HIIE2.5h) after the consumption of a standardized breakfast. An ad libitum buffet was offered 3.5h after the completion of the breakfast. Absolute energy intake (EI) and relative energy intake (REI) (relative energy intake = energy intake - energy expenditure from exercise) were measured. Appetite (hunger, fullness and desire for specific foods) scores and circulating concentration of insulin and IL-6 were determined at 1h, 1.75h, 2.5h and 3.25h after breakfast while lactate was measured post-exercise. EI was greater after the CTRL session compared to HIIE2.5h (5045.9 ±â€¯1873.5 kJ vs. 3716.1 ±â€¯1688.7 kJ). REI was greater for the CTRL session (5045.9 ±â€¯1873.5 kJ) than HIIE1h (3386.5 ±â€¯1660.1 kJ), HIIE2.5h (2508.5 ±â€¯1709.3 kJ) and SSE2.5h (3426.6 ±â€¯1788.0 kJ). Higher hunger scores were observed following the CRTL session with respect to those of HIIE2.5h. Insulin and IL-6 concentrations were greater after HIIE1h and SSE1h with respect to those obtained after HIIE2.5h, SSE2.5h and CTRL. Lactate concentrations were higher in HIIE1h and HIIE2.5h compared to those of SSE1h and SSE2.5h. These results show that HIIE performed 2.5h after a breakfast reduced appetite (hunger scores) and EI through mechanism that need to be characterized. This approach can be applied to individuals aiming to create an energetic deficit.

A Short-Term High-Fat Diet Alters Glutathione Levels and IL-6 Gene Expression in Oxidative Skeletal Muscles of Young Rats.

Obesity and ensuing disorders are increasingly prevalent worldwide. High-fat diets (HFD) and diet-induced obesity have been shown to induce oxidative stress and inflammation while altering metabolic homeostasis in many organs, including the skeletal muscle. We previously observed that 14 days of HFD impairs contractile functions of the soleus (SOL) oxidative skeletal muscle. However, the mechanisms underlying these effects are not clarified. In order to determine the effects of a short-term HFD on skeletal muscle glutathione metabolism, young male Wistar rats (100-125 g) were fed HFD or a regular chow diet (RCD) for 14 days. Reduced (GSH) and disulfide (GSSG) glutathione levels were measured in the SOL. The expression of genes involved in the regulation of glutathione metabolism, oxidative stress, antioxidant defense and inflammation were measured by RNA-Seq. We observed a significant 25% decrease of GSH levels in the SOL muscle. Levels of GSSG and the GSH:GSSG ratio were similar in both groups. Further, we observed a 4.5 fold increase in the expression of pro-inflammatory cytokine interleukin 6 (IL-6) but not of other cytokines or markers of inflammation and oxidative stress. We hereby demonstrate that a short-term HFD significantly lowers SOL muscle GSH levels. This effect could be mediated through the increased expression of IL-6. Further, the skeletal muscle antioxidant defense could be impaired under cellular stress. We surmise that these early alterations could contribute to HFD-induced insulin resistance observed in longer protocols.

Ethical consideration and feasibility demonstration of high-intensity interval training without the use of electrical shocks in mice with and without doxorubicin exposition.

INTRODUCTION: Most protocols intended to stimulate cardiovascular training in mice use electrical shocks that cause psychological stress and interfere with running performance. The aim of this study was to: 1) demonstrate the feasibility of a two-week high-intensity interval training (HIIT) program without the use of electric shocks in mice and 2) show that HIIT without electric shocks is feasible in the specific context of mice exposed to chemotherapy (i.e., doxorubicin). METHODS: Ten C57bl/6 6-week-old female mice underwent a maximal exercise capacity test before and after two weeks of HIIT (five sessions per week) to measure their maximum running speed. The electrical stimulus was substituted by gently lifting the hind legs of the training mice using a tongue depressor. A second sample of ten C57bl/6 10-week-old female mice receiving a single intravenous injection of 20 mg/kg of doxorubicin underwent a single session of HIIT post-DOX using the same gentle stimulation method. RESULTS: After two weeks of HIIT without the use of electric shocks, non-treated mice had a significant increase in their maximal speed (4.4 m•min-1; P = 0.019). In DOX-treated mice, the compliance rate to run went from 100% during the acclimation period prior to doxorubicin treatment to 100% when HIIT was performed after the DOX treatment. Doxorubicin treatment seemed to affect exercise compliance in DOX-treated mice. Our study demonstrated that a two-week HIIT program in non-treated mice and a single HIIT session in DOX-treated mice are feasible. CONCLUSION: The use of electric shocks was not required to obtain acceptable exercise compliance and a significant change in mice physical capacity. Our technique to perform a treadmill maximal exercise capacity test was shown to be feasible, even in specific pathological conditions like chemotherapy infusion, and could become a reference for future research protocols aimed at reducing the impact of psychological stress caused by electric shocks in mice. This model of exercise training in mice introduces an alternative to ethical conduct standards in animal research.

Altered Lipid Metabolism Impairs Skeletal Muscle Force in Young Rats Submitted to a Short-Term High-Fat Diet.

Obesity and ensuing disorders are increasingly prevalent in young populations. Prolonged exposure to high-fat diets (HFD) and excessive lipid accumulation were recently suggested to impair skeletal muscle functions in rodents. We aimed to determine the effects of a short-term HFD on skeletal muscle function in young rats. Young male Wistar rats (100-125 g) were fed HFD or a regular chow diet (RCD) for 14 days. Specific force, resistance to fatigue and recovery were tested in extensor digitorum longus (EDL; glycolytic) and soleus (SOL; oxidative) muscles using an ex vivo muscle contractility system. Muscle fiber typing and insulin signaling were analyzed while intramyocellular lipid droplets (LD) were characterized. Expression of key markers of lipid metabolism was also measured. Weight gain was similar for both groups. Specific force was decreased in SOL, but not in EDL of HFD rats. Muscle resistance to fatigue and force recovery were not altered in response to the diets. Similarly, muscle fiber type distribution and insulin signaling were not influenced by HFD. On the other hand, percent area and average size of intramyocellular LDs were significantly increased in the SOL of HFD rats. These effects were consistent with the increased expression of several mediators of lipid metabolism in the SOL muscle. A short-term HFD impairs specific force and alters lipid metabolism in SOL, but not EDL muscles of young rats. This indicates the importance of clarifying the early mechanisms through which lipid metabolism affects skeletal muscle functions in response to obesogenic diets in young populations.