In addition to their antibiotic effect, macrolides appear to modulate the inflammatory response in cystic fibrosis (CF) and could influence oxidative stress. The objective of this study was to assess ...oxidation biomarkers and levels of inflammation and to determine whether there is an association between these parameters and the intake of macrolides.
The subjects included in this cross-sectional study were, on the one hand, clinically stable patients with CF and, on the other, healthy controls. The following serum and plasma inflammatory and oxidative stress biomarkers were measured: interleukin-6 (IL-6), reactive C protein (RCP), tumor necrosis alpha (TNF-α), glutathione peroxidase (GPx), total antioxidant capacity (TAC), catalase (CAT), and superoxide dismutase (SOD), together with markers of lipid peroxidation (8-isoprostanes and thiobarbituric acid reactive substances TBARS). Clinical, anthropometric, lung function, radiological, and analytical variables (albumin, prealbumin, vitamins, and zinc) were also recorded.
We studied 36 adults with CF and 41 controls. No differences were observed in age, gender, or anthropometric variables. The patients had significantly higher levels of IL-6, TNF-α, RCP, TBARS, and isoprostanes, and lower levels of SOD than the controls. Twenty-three of the patients were treated with azithromycin, and they had more severe clinical and radiological parameters than those who were not but nevertheless presented significantly lower levels of TNF-α. No differences were observed in the markers of oxidation.
Inflammation and oxidation biomarkers were increased in patients with CF compared with controls. The use of azithromycin was associated with reduced TNF-α levels and did not influence oxidation parameters.
Zinc-α(2) glycoprotein (ZAG) stimulates lipid loss by adipocytes and may be involved in the regulation of adipose tissue metabolism. However, to date no studies have been made in the most extreme of ...obesity. The aims of this study are to analyze ZAG expression levels in adipose tissue from morbidly obese patients, and their relationship with lipogenic and lipolytic genes and with insulin resistance (IR).
mRNA expression levels of PPARγ, IRS-1, IRS-2, lipogenic and lipolytic genes and ZAG were quantified in visceral (VAT) and subcutaneous adipose tissue (SAT) of 25 nondiabetic morbidly obese patients, 11 with low IR and 14 with high IR. Plasma ZAG was also analyzed.
The morbidly obese patients with low IR had a higher VAT ZAG expression as compared with the patients with high IR (p = 0.023). In the patients with low IR, the VAT ZAG expression was greater than that in SAT (p = 0.009). ZAG expression correlated between SAT and VAT (r = 0.709, p<0.001). VAT ZAG expression was mainly predicted by insulin, HOMA-IR, plasma adiponectin and expression of adiponectin and ACSS2. SAT ZAG expression was only predicted by expression of ATGL.
ZAG could be involved in modulating lipid metabolism in adipose tissue and is associated with insulin resistance. These findings suggest that ZAG may be a useful target in obesity and related disorders, such as diabetes.
Background The percentage of excess weight lost (%EWL) after bariatric surgery (BS) shows great discrepancies from one individual to another. Objective To evaluate the %EWL one year after BS and to ...determine the existence of baseline biomarkers associated with weight loss. Methods We studied 329 patients with morbid obesity undergoing three types of BS (biliopancreatic diversion (BPD), Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG)), depending on the %EWL one year after surgery: good responders (GR) (%EWL ≥ 50%) and non-responders (NR) (%EWL < 50%). Results The GR presented a higher percentage of change in anthropometric and biochemical variables compared to the NR group, even within each type of BS. There was a greater percentage of GR among those who underwent RYGB. The patients who underwent SG showed the lowest decrease in biochemical variables, both in GR and NR. Within the GR group, those with a lower age showed greater improvement compared to the other age groups. A %EWL ≥50% was negatively associated with the age and atherogenic index of plasma (AIP), and positively with the type of BS (RYGB). Conclusions The GR group was associated with lower age and AIP and undergoing RYGB. Additionally, those patients who underwent SG showed a lower metabolic improvement.
Abstract The Spanish paradox is a phenomenon observed in Spain and some other Mediterranean countries by which the cardiovascular morbidity and mortality levels are dissociated from their ...cardiovascular risk factors. The Mediterranean diet has been proposed as the main reason for this dissociation, but dietary changes themselves are not enough to explain this situation. It has been recently discovered that Stearoil-CoA desaturase (SCD) is involved in the dissociation between a favourable atherogenic metabolic profile and the risk for arteriosclerosis. We propose a hypothesis that attempts to clarify the Spanish paradox. This hypothesis contemplates the essential role of dietary olive oil and its interaction with different SCD genetic patterns. Confirmation of this hypothesis could provide the basis for the design of clinical and preventive strategies against cardiovascular morbidity and mortality, as well as certain metabolic risk factors.
Context: Adipose tissue hypoxia and endoplasmic reticulum (ER) stress may link the presence of chronic inflammation and macrophage infiltration in severely obese subjects. We previously reported the ...up-regulation of TNF-like weak inducer of apoptosis (TWEAK)/ fibroblast growth factor-inducible 14 (Fn14) axis in adipose tissue of severely obese type 2 diabetic subjects.
Objectives: The objective of the study was to examine TWEAK and Fn14 adipose tissue expression in obesity, severe obesity, and type 2 diabetes in relation to hypoxia and ER stress.
Design: In the obesity study, 19 lean, 28 overweight, and 15 obese nondiabetic subjects were studied. In the severe obesity study, 23 severely obese and 35 control subjects were studied. In the type 2 diabetes study, 11 type 2 diabetic and 36 control subjects were studied. The expression levels of the following genes were analyzed in paired samples of sc and visceral adipose tissue: Fn14, TWEAK, VISFATIN, HYOU1, FIAF, HIF-1a, VEGF, GLUT-1, GRP78, and XBP-1. The effect of hypoxia, inflammation, and ER stress on the expression of TWEAK and Fn14 was examined in human adipocyte and macrophage cell lines.
Results: Up-regulation of TWEAK/Fn14 and hypoxia and ER stress surrogate gene expression was observed in sc and visceral adipose tissue only in our severely obese cohort. Hypoxia modulates TWEAK or Fn14 expression in neither adipocytes nor macrophages. On the contrary, inflammation up-regulated TWEAK in macrophages and Fn14 expression in adipocytes. Moreover, TWEAK had a proinflammatory effect in adipocytes mediated by the nuclear factor-κB and ERK but not JNK signaling pathways.
Conclusions: Our data suggest that TWEAK acts as a pro-inflammatory cytokine in the adipose tissue and that inflammation, but not hypoxia, may be behind its up-regulation in severe obesity.
Inflammation but not hypoxia may be behind the up-regulation of TWEAK/Fn14 gene expression levels in SAT and VAT adipose tissue depots of severely obese patients.
Little is known about the jejunal insulin signalling pathways in insulin resistance/diabetes states and their possible regulation by insulin/leptin. We study in jejunum the relation between insulin ...signalling and insulin resistance in morbidly obese subjects with low (MO-low-IR) or with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2DM)), and the effect of insulin/leptin on intestinal epithelial cells (IEC). Insulin receptor substrate-1 (IRS1) and the catalytic p110β subunit (p110β) of phosphatidylinositol 3-kinase (PI3K) were higher in MO-high-IR than in MO-low-IR. The regulatory p85α subunit of PI3K (p85α)/p110β ratio was lower in MO-high-IR and MO-metf-T2DM than in MO-low-IR. Akt-phosphorylation in Ser473 was reduced in MO-high-IR compared with MO-low-IR. IRS1 and p110-β were associated with insulin and leptin levels. The improvement of body mass index (BMI) and HOMA-IR (homeostasis model assessment of insulin resistance index) after bariatric surgery was associated with a higher IRS1 and a lower p85α/p110β ratio. IEC (intestinal epithelial cells) incubation with a high glucose + insulin dose produced an increase of p85α and p110β. High dose of leptin produced an increase of IRS1, p85α and p110β. In conclusion, despite the existence of insulin resistance, the jejunal expression of genes involved in insulin signalling was increased in MO-high-IR. Their expressions were regulated mainly by leptin. IRS1 and p85α/p110β ratio was associated with the evolution of insulin resistance after bariatric surgery.
The changes in the transcriptomic profiling of subcutaneous adipose tissue (SAT) when weight loss stabilizes after a Roux-en-Y gastric bypass (RYGB) are still largely unknown.
To investigate the ...changes produced in SAT gene expression of morbidly obese women when their weight loss stabilizes 2 years after RYGB.
University hospital.
SAT biopsies of the periumbilical area were taken before and 2 years after RYGB. Gene expression levels were assessed by microarray analysis and significant differences in gene expression were validated by real-time quantitative polymerase chain reaction. The findings were also confirmed in an independent population of morbidly obese women.
Microarray analysis revealed that the overexpressed differentially expressed genes have a prominent role in the pathways involved in biosynthetic processes, especially lipid or carboxylic ones (stearoyl-Coenzyme A desaturase-1, fatty acid desaturase-1, fatty acid elongase-6, ATP citrate lyase, fatty acid synthase, lipin-1, monoacylglycerol O-acyltransferase, patatin-like phospholipase domain containing-3, phosphate cytidylyltransferase-2, cholesteryl ester transfer protein, transmembrane 7 superfamily member 2, pyruvate carboxylase, and glycogen synthase 2). Most of the underexpressed differentially expressed genes are related with immune system and inflammation processes (immune responses, response to stress, cell death, regulation of biological quality, immune effector process, the response to endogenous stimulus, and the response to other types of stimulus).
An improvement of the SAT inflammatory and immune profile and an induction of genes involved in the regulation of lipid metabolism are shown when weight loss stabilizes 2 years after RYGB. Most of the genes shown are clearly linked to obesity and other metabolic disorders.
Little information exists in humans on the regulation that oxidized low-density lipoprotein (oxLDL) exerts on adipocyte metabolism, which is associated with obesity and type 2 diabetes. The aim was ...to analyze the oxLDL effects on adipocytokine secretion and scavenger receptors (SRs) and cell death markers in human visceral adipocytes. Human differentiated adipocytes from visceral adipose tissue from non-obese and morbidly obese subjects were incubated with increasing oxLDL concentrations. mRNA expression of SRs, markers of apoptosis and autophagy, secretion of adipocytokines, and glucose uptake were analyzed. In non-obese and in morbidly obese subjects, oxLDL produced a decrease in insulin-induced glucose uptake, a significant dose-dependent increase in tumor necrosis factor-α (TNF-α), IL-6, and adiponectin secretion, and a decrease in leptin secretion. OxLDL produced a significant increase of
and a decrease in
and
expression. The expression of
(marker of apoptosis, necrosis and autophagy) was significantly increased and
(antiapoptotic marker) was decreased. OxLDL could sensitize adipocytes to a lower insulin-induced glucose uptake, a more proinflammatory phenotype, and could modify the gene expression involved in apoptosis, autophagy, necrosis, and mitophagy. OxLDL can upregulate
, and this could lead to a possible amplification of proinflammatory and proapoptotic effects of oxLDL.
Background: The effects of different types of fatty acids on the gene expression of key players in the IRS1/PI3K signaling pathway have been poorly studied. Material and Methods: We analyzed IRS1, ...p85α, and p110β mRNA expression and the fatty acid composition of phospholipids in visceral adipose tissue from patients with morbid obesity and from non-obese patients. Moreover, we analyzed the expression of those genes in visceral adipocytes incubated with oleic, linoleic, palmitic and dosahexaenoic acids. Results: We found a reduced IRS1 expression in patients with morbid obesity, independent of insulin resistance, and a reduced p110β expression in those with lower insulin resistance. A positive correlation was found between p85α and stearic acid, and between IRS1 and p110β with palmitic and dosahexaenoic acid. In contrast, a negative correlation was found between p85α and oleic acid, and between IRS1 and p110β with linoleic, arachidonic and adrenic acid. Incubation with palmitic acid decreased IRS1 expression. p85α was down-regulated after incubation with oleic and dosahexaenoic acid and up-regulated with palmitic acid. p110β expression was increased and decreased after incubation with oleic and palmitic acid, respectively. The ratio p85α/p110β was decreased by oleic and dosahexaenoic acid and increased by palmitic acid. Conclusions: Our in vitro results suggest a detrimental role of palmitic acid on the expression of gene related to insulin signaling pathway, with oleic acid being the one with the higher and more beneficial effects. DHA had a slight beneficial effect. Fatty acid-induced regulation of genes related to the IRS1/PI3K pathway may be a novel mechanism by which fatty acids regulate insulin sensitivity in visceral adipocytes.
Background: Intragastric injection of botulinum toxin A (BT-A) has been shown to be effective for weight loss up to six months after administration, according to previous studies. Our objective was ...to determine, in patients on bariatric surgery waiting lists, the effect of BT-A on weight loss in the pre- and postoperative period and to analyse if there are different responses based on Body Mass Index (BMI). Methods: We performed a follow-up analysis of the IntraTox study, which included 46 patients on bariatric surgery waiting lists in a single-centre, randomised, double-blind, placebo-controlled clinical trial. The treatment group received intragastric BT-A, whereas the control group received physiological saline solution. The one-time procedure was performed at the time of diagnostic endoscopy 7−8 months before surgery. Weight loss was evaluated at admission and after 4 and 12 weeks from the bariatric surgery. Our analysis was stratified by BMI at randomisation. Results: weight loss percentage on the day of surgery, with respect to the initial visit, was −4.5 ± 3.9% for the control group vs. −7.6 ± 4.2%, for the treatment group (p = 0.013). Weight loss percentage tended to remain greater in the treatment group one month after the intervention (−12.7 ± 4.7% vs. −15.2 ± 4.6%, p = 0.07) and become similar three months after (−21.6 ± 4.7% vs. −21.6 ± 4.6%). After stratifying by BMI, only patients with BMI over 50 kg/m2 allocated to the treatment group obtained a greater weight loss at the end of the trial, the day of surgery, and one month after, compared with the placebo group (−4.9 ± 4.9%, −10.8 ± 5.3% and −17.1 ± 3.8% vs. −0.1 ± 2.6%, −4.3 ± 3.2% and −12.8 ± 4.1%, respectively (p < 0.05). Conclusions: intragastric injection of BT-A is effective to achieve significant weight loss, especially in extreme obesity. Its use before bariatric surgery enhances perioperative weight loss.
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