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.

Immunometabolic Changes in Hepatocytes Arising from Obesity and the Practice of Physical Exercise.

Over the recent years, a particular interest was shown towards understanding the roles of excessive hepatic fat accumulation and the development of obesity-related diseases. While hepatic triacylglycerol accumulation seems to be a response to the systemic increase of insulin release, fatty acid metabolites contribute to the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). It is widely accepted that NAFLD is a polygenic and multifactorial disease under the influence of critical behavioral factors such as overeating and sedentary lifestyles. The progression of the disease is proposed to include the accumulation of lipids in hepatocytes, but liver damage would be mainly initiated through an exaggerated activation of the immune system. This inflammatory response would be triggered by the increase in cytokine production followed by TLR-4 activation and NF-kB pathways. Interestingly, cytokines as IL-1ra, IL-4, IL-6 and IL-10 act as antiinflammatory in response to exercise and thus, could play an important role in the restoration of liver functions in diseased conditions. Strategies for healthy life behaviors including nutrition and regular physical exercise are recommended to counteract the dreadful effects of NAFLD. To beyond the classical effect of exercise for increasing energy expenditure and/or inducing negative energy balance, exercise also prevents and reverses the effects of disorders related to the immunometabolic profile. This suggests that exercise prescription may be an attractive alternative for the prevention of obesity and NAFLD. Thus, this review seeks to shed light on the inflammatory pathways regulating the beneficial effects of physical activity on obesity and NAFLD. We will clarify how physical activity intervenes to normalize inflammatory processes and prevent obesity and NAFLD. Finally, the exercise interventions should be individualized to facilitate behavioral and cognitive strategies in order to promote long-term adherence. A multidisciplinary approach including lifestyles, diet and exercise training interventions is considered as a "best practice" and displays the strongest liver benefits when it occurs simultaneously with weight loss.

Altered Feeding Behaviors and Adiposity Precede Observable Weight Gain in Young Rats Submitted to a Short-Term High-Fat Diet.

Information regarding the early effects of obesogenic diets on feeding patterns and behaviors is limited. To improve knowledge regarding the etiology of obesity, young male Wistar rats were submitted to high-fat (HFD) or regular chow diets (RCDs) for 14 days. Various metabolic parameters were continuously measured using metabolic chambers. Total weight gain was similar between groups, but heavier visceral fat depots and reduced weight of livers were found in HFD rats. Total calorie intake was increased while individual feeding bouts were shorter and of higher calorie intake in response to HFD. Ambulatory activity and sleep duration were decreased in HFD rats during passive and active phase, respectively. Acylated and unacylated ghrelin levels were unaltered by the increased calorie intake and the early changes in body composition. This indicates that at this early stage, the orexigenic signal did not adapt to the high-calorie content of HFD. We hereby demonstrate that, although total weight gain is not affected, a short-term obesogenic diet alters body composition, feeding patterns, satiation, ambulatory activity profiles, and behaviours in a young rat model. Moreover, this effect precedes changes in weight gain, obesity, and ensuing metabolic disorders.

The impact of a short-term high-fat diet on mitochondrial respiration, reactive oxygen species production, and dynamics in oxidative and glycolytic skeletal muscles of young rats.

Multiple aspects of mitochondrial function and dynamics remain poorly studied in the skeletal muscle of pediatric models in response to a short-term high-fat diet (HFD). This study investigated the impact of a short-term HFD on mitochondrial function and dynamics in the oxidative soleus (SOL) and glycolytic extensor digitorum longus (EDL) muscles in young rats. Young male Wistar rats were submitted to either HFD or normal chow (NCD) diets for 14 days. Permeabilized myofibers from SOL and EDL were prepared to assess mitochondrial respiration and reactive oxygen species (ROS) production. The expression and content of protein involved in mitochondrial metabolism and dynamics (fusion/fission) were also quantified. While no effects of HFD was observed on mitochondrial respiration when classical complex I and II substrates were used, both SOL and EDL of rats submitted to a HFD displayed higher basal and ADP-stimulated respiration rates when Malate + Palmitoyl-L-carnitine were used as substrates. HFD did not alter ROS production and markers of mitochondrial content. The expression of CPT1b was significantly increased in SOL and EDL of HFD rats. Although the expression of UCP3 was increased in SOL and EDL muscles from HFD rats, mitochondrial coupling efficiency was not altered. In SOL of HFD rats, the transcript levels of Mfn2 and Fis1 were significantly upregulated. The expression and content of proteins regulating mitochondrial dynamics was not modulated by HFD in the EDL. Finally, DRP1 protein content was increased by over fourfold in the SOL of HFD rats. Taken altogether, our findings show that exposing young animals to short-term HFD results in an increased capacity of skeletal muscle mitochondria to oxidize fatty acids, without altering ROS production, coupling efficiency, and mitochondrial content. Our results also highlight that the impact of HFD on mitochondrial dynamics appears to be muscle specific.

Bariatric Surgery-Induced Resolution of Hypertension and Obstructive Sleep Apnea: Impact of Modulation of Body Fat, Ectopic Fat, Autonomic Nervous Activity, Inflammatory and Adipokine Profiles.

BACKGROUND: Obesity-associated systemic hypertension (HTN) and obstructive sleep apnea (OSA) have multiple pathophysiological pathways including ectopic fat deposition, inflammation, altered adipokine profile, and increased sympathetic nervous activity. We characterized these potential mechanisms in severely obese patients with or without HTN and OSA. We also compared changes of these mechanisms at 12 months following biliopancreatic diversion with duodenal switch (BPD-DS) surgery according to HTN and OSA resolution. METHODS: Sixty-two severely obese patients were evaluated at baseline and 12 months; 40 patients underwent BPD-DS. Blood samples, bioelectrical impedance analysis, computed tomography scan, and 24-h heart rate monitoring were performed. OSA have been determined with polysomnography and HTN with blood pressure measurement and medical file. RESULTS: Patients with HTN (n = 35) and OSA (n = 32) were older men with higher ectopic fat deposition and lower parasympathetic nervous activity without difference in adipokines and inflammatory markers. Lower reduction in weight was observed in patients with unresolved HTN (-40.9 ± 3.3 kg vs. -55.6 ± 3.8 kg; p = 0.001) and OSA (-41.4 ± 10.7 kg vs. -51.0 ± 15.2 kg; p = 0.006). Visceral adipose tissue reduction was lower in patients with unresolved HTN (-171.0 ± 25.7 cm2 vs. -274.5 ± 29.0 cm2; p = 0.001) in contrast to a trend for lower abdominal subcutaneous adipose tissue reduction in patients with unresolved OSA (-247.7 ± 91.5 cm2 vs. -390.5 ± 109.1 cm2; p = 0.08). At 12 months, parasympathetic activity was lowest in unresolved HTN and OSA patients, without difference in adipokines and inflammatory biomarkers. CONCLUSION: Lower ectopic fat mobilization, lower level of parasympathetic nervous activity, and lower subcutaneous adiposity mobilization may play a role in the pathophysiology of unresolved HTN and OSA following BPD-DS surgery.

Association between nesfatin-1 levels and metabolic improvements in severely obese patients who underwent biliopancreatic derivation with duodenal switch.

CONTEXT: Nesfatin-1 is a neuroendocrine peptide with potent anorexigenic activity in rodents. The potential role of nesfatin-1 on the regulation of energy balance, metabolic functions and inflammation is currently debated in obese humans. In the present study, nesfatin-1 fluctuations and their associations with metabolic factors were investigated in severely obese patients who underwent biliopancreatic diversion with duodenal switch (BPD/DS) and severely obese controls (SOC). BASIC PROCEDURES: Sixty severely obese patients who underwent BPD/DS and 15 SOC (matched for BMI and age) were included in the study. Associations between nesfatin-1 levels and body composition, glucose metabolism, lipid profile as well as inflammatory markers were evaluated at baseline and over a post-surgery12-month (12M) period. MAIN FINDINGS: Body weight was reduced at 6M and at 12M in BPD/DS patients (P<0.001). Nesfatin-1 levels were reduced at 6M (women: P<0.05) and at 12M (men and women; P<0.001) in BPD/DS patients. At baseline, nesfatin-1 levels negatively correlated with weight, fat (FM) and fat-free mass (FFM) in the whole population (combined BPD/DS and SOC patients). At 12M, nesfatin-1 concentrations positively correlated with weight, FM, fasting insulin, insulin resistance, total cholesterol, LDL-cholesterol, triglyceride and apoB values. At 12M, % changes in nesfatin-1 were positively associated with% changes in weight, FM, FFM, fasting insulin, insulin resistance, total cholesterol, LDL-cholesterol, apoB and C-reactive protein. CONCLUSION: Nesfatin-1 levels decrease following BPD/DS-induced weight loss and are significantly associated with parameters of metabolic health.

Effect of an Acute High Carbohydrate Diet on Body Composition Using DXA in Young Men.

AIM: The aim of this study is to investigate the effect of a 3-day high-carbohydrate diet (≥75% of total calories) on body composition using dual-energy X-ray absorptiometry (DXA). METHODS: Twenty non-obese young men (age 22.7 ± 2.6 years, BMI 23.5 ± 2.1 kg/m(2)) completed the study. Two DXA tests were performed for the measurement of total body weight, body mass index (BMI), body fat percentage as well as total, appendicular and central lean body mass (LBM) before and after a high-carbohydrate diet for 3 days. In addition, the participants completed a food diary during the 3-day high-carbohydrate diet to determine the mean percentage of carbohydrates consumed from total kilocalories. RESULTS: The mean percentage of carbohydrate intake over 3 days was 83.7 ± 8.4%. Our results showed a significant increase in total body weight, BMI as well as total and appendicular LBM after the high-carbohydrate diet (p < 0.01). In addition, we observed a strong tendency for lower body fat percentage values after the intervention (p = 0.05). No significant difference was observed for central LBM. CONCLUSIONS: These results indicate that the effect of an acute high carbohydrate diet seems to affect body composition values using DXA, such as total LBM. This study may lead to the need of standardizing a diet prior to using DXA.

Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice.

Skeletal muscle aging is associated with a progressive decline in muscle mass and strength, a process termed sarcopenia. Evidence suggests that accumulation of mitochondrial dysfunction plays a causal role in sarcopenia, which could be triggered by impaired mitophagy. Mitochondrial function, mitophagy and mitochondrial morphology are interconnected aspects of mitochondrial biology, and may coordinately be altered with aging. However, mitochondrial morphology has remained challenging to characterize in muscle, and whether sarcopenia is associated with abnormal mitochondrial morphology remains unknown. Therefore, we assessed the morphology of SubSarcolemmal (SS) and InterMyoFibrillar (IMF) mitochondria in skeletal muscle of young (8-12wk-old) and old (88-96wk-old) mice using a quantitative 2-dimensional transmission electron microscopy approach. We show that sarcopenia is associated with larger and less circular SS mitochondria. Likewise, aged IMF mitochondria were longer and more branched, suggesting increased fusion and/or decreased fission. Accordingly, although no difference in the content of proteins regulating mitochondrial dynamics (Mfn1, Mfn2, Opa1 and Drp1) was observed, a mitochondrial fusion index (Mfn2-to-Drp1 ratio) was significantly increased in aged muscles. Our results reveal that sarcopenia is associated with complex changes in mitochondrial morphology that could interfere with mitochondrial function and mitophagy, and thus contribute to aging-related accumulation of mitochondrial dysfunction and sarcopenia.

Crosstalk between intestinal microbiota, adipose tissue and skeletal muscle as an early event in systemic low-grade inflammation and the development of obesity and diabetes.

Obesity is associated with a systemic chronic low-grade inflammation that contributes to the development of metabolic disorders such as cardiovascular diseases and type 2 diabetes. However, the etiology of this obesity-related pro-inflammatory process remains unclear. Most studies have focused on adipose tissue dysfunctions and/or insulin resistance in skeletal muscle cells as well as changes in adipokine profile and macrophage recruitment as potential sources of inflammation. However, low-grade systemic inflammation probably involves a complex network of signals interconnecting several organs. Recent evidences have suggested that disturbances in the composition of the gut microbial flora and alterations in levels of gut peptides following the ingestion of a high-fat diet may be a cause of low-grade systemic inflammation that may even precede and predispose to obesity, metabolic disorders or type 2 diabetes. This hypothesis is appealing because the gastrointestinal system is first exposed to nutrients and may thereby represent the first link in the chain of events leading to the development of obesity-associated systemic inflammation. Therefore, the present review will summarize the latest advances interconnecting intestinal mucosal bacteria-mediated inflammation, adipose tissue and skeletal muscle in a coordinated circuitry favouring the onset of a high-fat diet-related systemic low-grade inflammation preceding obesity and predisposing to metabolic disorders and/or type 2 diabetes. A particular emphasis will be given to high-fat diet-induced alterations of gut homeostasis as an early initiator event of mucosal inflammation and adverse consequences contributing to the promotion of extended systemic inflammation, especially in adipose and muscular tissues.

Interrelationships between ghrelin, insulin and glucose homeostasis: Physiological relevance.

Ghrelin is a 28 amino acid peptide mainly derived from the oxyntic gland of the stomach. Both acylated (AG) and unacylated (UAG) forms of ghrelin are found in the circulation. Initially, AG was considered as the only bioactive form of ghrelin. However, recent advances indicate that both AG and UAG exert distinct and common effects in organisms. Soon after its discovery, ghrelin was shown to promote appetite and adiposity in animal and human models. In response to these anabolic effects, an impressive number of elements have suggested the influence of ghrelin on the regulation of metabolic functions and the development of obesity-related disorders. However, due to the complexity of its biochemical nature and the physiological processes it governs, some of the effects of ghrelin are still debated in the literature. Evidence suggests that ghrelin influences glucose homeostasis through the modulation of insulin secretion and insulin receptor signaling. On the other hand, insulin was also shown to influence circulating levels of ghrelin. Here, we review the relationship between ghrelin and insulin and we describe the impact of this interaction on the modulation of glucose homeostasis.

Substance P decreases fat storage and increases adipocytokine production in 3T3-L1 adipocytes.

Obesity, inflammation, and insulin resistance are closely linked. Substance P (SP), via its neurokinin 1 receptor (NK1R), mediates inflammatory and, possibly, neuroendocrine processes. We examined SP effects on lipid storage and cytokine production in 3T3-L1 adipocytes and adipose tissues. 3T3-L1 adipocytes and preadipocytes express NK1R, and 8 days of SP supplementation during differentiation to 3T3-L1 preadipocytes decreased lipid droplet accumulation. SP (10 nM, 24 h) increased lipolysis in primary adipocytes (138 ± 7%, P < 0.05) and reduced fatty acid uptake (-31 ± 7%, P < 0.05) and mRNA expression of the differentiation-related transcription factors peroxisome proliferator-activated receptor-γ type 2 (-64 ± 2%, P < 0.001) and CCAAT enhancer-binding protein (CEBP)-α (-65 ± 2%, P < 0.001) and the lipid storage genes fatty acid-binding protein type 4 (-59 ± 2%, P < 0.001) and diacylglycerol O-acyltransferase-1 (-45 ± 2%, P < 0.01) in 3T3-L1 adipocytes, while CD36, a fatty acid transporter (+82 ± 19%, P < 0.01), was augmented. SP increased secretion of complement C3 (148 ± 15%, P < 0.04), monocyte chemoattractant protein-1 (156 ± 16%, P < 0.03), and keratinocyte-derived chemokine (148 ± 18%, P = 0.045) in 3T3-L1 adipocytes and monocyte chemoattractant protein-1 (496 ± 142%, P < 0.02) and complement C3 (152 ± 25%, P < 0.04) in adipose tissue and primary adipocytes, respectively. These SP effects were accompanied by downregulation of insulin receptor substrate 1 (-82 ± 2%, P < 0.01) and GLUT4 (-76 ± 2%, P < 0.01) mRNA expression, and SP acutely blocked insulin-mediated stimulation of fatty acid uptake and Akt phosphorylation. Although adiponectin secretion was unchanged, mRNA expression was decreased (-86 ± 8%, P < 0.001). In humans, NK1R expression correlates positively with plasma insulin, fatty acid, and complement C3 and negatively with adiponectin, CEBPα, CEBPß, and peroxisome proliferator-activated receptor-γ mRNA expression in omental, but not subcutaneous, adipose tissue. Our results suggest that, beyond its neuroendocrine and inflammatory effects, SP could also be involved in targeting adipose tissue and influencing insulin resistance.