[Show abstract][Hide abstract] ABSTRACT: Chronic low-grade inflammation and uncontrolled metabolic stress response are cardinal features of obesity; a major risk factor for the development of diabetes. Dual specificity protein phosphatase 1 (DUSP1) is implicated in metabolism and energy expenditure. Mice lacking DUSP1 are resistant to high fat diet-induced obesity. However, the expression of DUSP1 has not been investigated in human obesity. In the current study, we compared the expression pattern of DUSP1 between lean and obese non-diabetic human subjects using subcutaneous adipose tissue and peripheral blood mononuclear cells. The levels of DUSP1 mRNA and protein were significantly increased in obese subjects with concomitant decrease in the phosphorylation of p38 MAPK and PGC-1α and an increase in the levels of phospho-JNK and phospho-ERK. Moreover, obese subjects had higher levels of circulating DUSP1 protein that correlated positively with various obesity indicators, triglycerides, glucagon, insulin, leptin and PAI-1 (P<0.05), but negatively with VO2, Max and high-density lipoprotein (P<0.05). The observation that DUSP1 was overexpressed in obese subjects prompted us to investigate if physical exercise could reduce its expression. In this study, we report for the first time that physical exercise significantly attenuated the expression of DUSP1 with a parallel increase in the expression of PGC-1α and a reduction in JNK and ERK activities along with attenuated inflammatory response. Collectively, our data suggest that DUSP1 upregulation is strongly linked to adiposity and physical exercise modulates its expression. This gives further evidence that exercise might be useful as a strategy for managing obesity and preventing its associated complications.
Full-text · Article · Nov 2014 · AJP Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Obesity is associated with adipose tissue inflammation that is involved
in the development of insulin resistance and type 2 diabetes.
The main source of inflammatory mediators in obese adipose tissue is
macrophages. Recent animal studies suggest that Th1 and CD8+ cytotoxic
T cells are detrimentally involved in the attraction and differentiation
of adipose tissue macrophages, whereas Th2 and,
predominantly, regulatory T cells (Tregs) act protective. IL-17, a proinflammatory
cytokine that is produced by several cell types, including
Th17 cells, is often associated with diseases that are characterised
by tissue inflammation. However, the role of these immune
cell types in obesity-associated adipose tissue inflammation has not
been well-defined in human. Therefore, we aimed in the present work
to compare the different immune cell types in the peripheral blood
and adipose tissue of lean and obese individuals with and without
Peripheral blood mononuclear cells and adipose tissue biopsies were
isolated from adult lean and obese subjects with and without diabetes
and immunological parameters were assessed.
Data on the imbalance of these immune cell types between lean and
obese subjects will be presented together with data on the level of
expression of specific markers as well as inflammatory and antiinflammatory
cytokine and biochemical profiles. The data presented
will generate the basic information required for developing an
immunodiagnostic and/or immunotherapeutic strategy aimed at
prevention/treatment of type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: Background
Obesity is characterized by a chronic low-grade inflammation and altered stress responses in key metabolic tissues. Impairment of heat shock response (HSR) has been already linked to diabetes and insulin resistance as reflected by decrease in heat shock proteins (HSPs) expression. However, the status of HSR in non-diabetic human obese has not yet been elucidated. The aim of the current study was to investigate whether obesity triggers a change in the HSR pattern and the impact of physical exercise on this pattern at protein and mRNA levels.
Two groups of adult non-diabetic human subjects consisting of lean and obese (n = 47 for each group) were enrolled in this study. The expression pattern of HSP-27, DNAJB3/HSP-40, HSP-60, HSC-70, HSP72, HSP-90 and GRP-94 in the adipose tissue was primarily investigated by immunohistochemistry and then complemented by western blot and qRT-PCR in Peripheral blood mononuclear cells (PBMCs). HSPs expression levels were correlated with various physical, clinical and biochemical parameters. We have also explored the effect of a 3-month moderate physical exercise on the HSPs expression pattern in obese subjects.
Obese subjects displayed increased expression of HSP-60, HSC-70, HSP-72, HSP-90 and GRP-94 and lower expression of DNAJB3/HSP-40 (P < 0.05). No differential expression was observed for HSP-27 between the two groups. Higher levels of HSP-72 and GRP-94 proteins correlated positively with the indices of obesity (body mass index and percent body fat) and circulating levels of IFN-gamma-inducible protein 10 (IP-10) and RANTES chemokines. This expression pattern was concomitant with increased inflammatory response in the adipose tissue as monitored by increased levels of Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), and RANTES (P < 0.05). Physical exercise reduced the expression of various HSPs in obese to normal levels observed in lean subjects with a parallel decrease in the endogenous levels of IL-6, TNF-α, and RANTES.
Taken together, these data indicate that obesity triggers differential regulation of various components of the HSR in non-diabetic subjects and a 3-month physical moderate exercise was sufficient to restore the normal expression of HSPs in the adipose tissue with concomitant attenuation in the inflammatory response.
Full-text · Article · Jul 2014 · Lipids in Health and Disease
[Show abstract][Hide abstract] ABSTRACT: Objective
Recent studies have demonstrated a protective role for IL-33 against obesity-associated inflammation, atherosclerosis and metabolic abnormalities. IL-33 promotes the production of T helper type 2 (Th2) cytokines, polarizes macrophages towards a protective alternatively activated phenotype, reduces lipid storage and decreases the expression of genes associated with lipid metabolism and adipogenesis. Our objective was to determine the level of serum IL-33 in non-diabetic and diabetic subjects, and to correlate these levels with clinical (BMI and body weight) and metabolic (serum lipids and HbA1c) parameters.
The level of IL-33 was measured in the serum of lean, overweight and obese non-diabetic and diabetic subjects, and then correlated with clinical and metabolic parameters.
Non-lean subjects had significantly (P = 0.01) lower levels of IL-33 compared to lean controls. IL-33 was negatively correlated with the BMI and body weight in lean and overweight, but not obese (non-diabetic and diabetic), subjects. IL-33 is associated with protective lipid profiles, and is negatively correlated with HbA1c, in non-diabetic (lean, overweight and obese) but not diabetic subjects.
Our data support previous findings showing a protective role for IL-33 against adiposity and atherosclerosis, and further suggest that reduced levels of IL-33 may put certain individuals at increased risk of developing atherosclerosis and insulin resistance. Therefore, IL-33 may serve as a novel marker to predict those who may be at increased risk of developing atherosclerosis.
[Show abstract][Hide abstract] ABSTRACT: RANTES and its CCR5 receptor trigger inflammation and its progression to insulin resistance in obese. In the present study, we investigated for the first time the effect of physical exercise on the expression of RANTES and CCR5 in obese humans. Fifty-seven adult nondiabetic subjects (17 lean and 40 obese) were enrolled in a 3-month supervised physical exercise. RANTES and CCR5 expressions were measured in PBMCs and subcutaneous adipose tissue before and after exercise. Circulating plasma levels of RANTES were also investigated. There was a significant increase in RANTES and CCR5 expression in the subcutaneous adipose tissue of obese compared to lean. In PBMCs, however, while the levels of RANTES mRNA and protein were comparable between both groups, CCR5 mRNA was downregulated in obese subjects (P < 0.05). Physical exercise significantly reduced the expression of both RANTES and CCR5 (P < 0.05) in the adipose tissue of obese individuals with a concomitant decrease in the levels of the inflammatory markers TNF- α , IL-6, and P-JNK. Circulating RANTES correlated negatively with anti-inflammatory IL-1ra (P = 0.001) and positively with proinflammatory IP-10 and TBARS levels (P < 0.05). Therefore, physical exercise may provide an effective approach for combating the deleterious effects associated with obesity through RANTES signaling in the adipose tissue.
Full-text · Article · Apr 2014 · Mediators of Inflammation
[Show abstract][Hide abstract] ABSTRACT: Sedentary lifestyle and excessive energy intake are prominent contributors to obesity; a major risk factors for the development of insulin resistance, type 2 diabetes and cardiovascular diseases. Elucidating the molecular mechanisms underlying these chronic conditions is of relevant importance as it might lead to the identification of novel anti-obesity targets. The purpose of the current study is to investigate differentially expressed proteins between lean and obese subjects through a shot-gun quantitative proteomics approach using peripheral blood mononuclear cells (PBMCs) extracts as well as potential modulation of those proteins by physical exercise. Using this approach, a total of 47 proteins showed at least 1.5 fold change between lean and obese subjects. In obese, the proteomic profiling before and after 3 months of physical exercise showed differential expression of 38 proteins. Thrombospondin 1 (TSP1) was among the proteins that were upregulated in obese subjects and then decreased by physical exercise. Conversely, the histone deacetylase 4 (HDAC4) was downregulated in obese subjects and then induced by physical exercise. The proteomic data was further validated by qRT-PCR, Western blot and immunohistochemistry in both PBMCs and adipose tissue. We also showed that HDAC4 levels correlated positively with maximum oxygen consumption (VO2 Max) but negatively with body mass index, percent body fat, and the inflammatory chemokine RANTES. In functional assays, our data indicated that ectopic expression of HDAC4 significantly impaired TNF-α-dependent activation of NF-κB, establishing thus a link between HDAC4 and regulation of the immune system. Together, the expression pattern of HDAC4 in obese subjects before and after physical exercise, its correlation with various physical, clinical and metabolic parameters along with its inhibitory effect on NF-κB are suggestive of a protective role of HDAC4 against obesity. HDAC4 could therefore represent a potential therapeutic target for the control and management of obesity and presumably insulin resistance.
[Show abstract][Hide abstract] ABSTRACT: Obesity is a major risk factor for a myriad of disorders such as insulin resistance and diabetes. The mechanisms underlying these chronic conditions are complex but low grade inflammation and alteration of the endogenous stress defense system are well established. Previous studies indicated that impairment of HSP-25 and HSP-72 was linked to obesity, insulin resistance and diabetes in humans and animals while their induction was associated with improved clinical outcomes. In an attempt to identify additional components of the heat shock response that may be dysregulated by obesity, we used the RT(2)-Profiler PCR heat shock array, complemented with RT-PCR and validated by Western blot and immunohistochemistry. Using adipose tissue biopsies and PBMC of non-diabetic lean and obese subjects, we report the downregulation of DNAJB3 cochaperone mRNA and protein in obese that negatively correlated with percent body fat (P = 0.0001), triglycerides (P = 0.035) and the inflammatory chemokines IP-10 and RANTES (P = 0.036 and P = 0.02, respectively). DNAJB positively correlated with maximum oxygen consumption (P = 0.031). Based on the beneficial effect of physical exercise, we investigated its possible impact on DNAJB3 expression and indeed, we found that exercise restored the expression of DNAJB3 in obese subjects with a concomitant decrease of phosphorylated JNK. Using cell lines, DNAJB3 protein was reduced following treatment with palmitate and tunicamycin which is suggestive of the link between the expression of DNAJB3 and the activation of the endoplasmic reticulum stress. DNAJB3 was also shown to coimmunoprecipiate with JNK and IKKβ stress kinases along with HSP-72 and thus, suggesting its potential role in modulating their activities. Taken together, these data suggest that DNAJB3 can potentially play a protective role against obesity.
[Show abstract][Hide abstract] ABSTRACT: Osteopontin (OPN) and IL-18 are known inflammatory mediators and both participate in a wide range of biological processes linked to immunological disorders. Since an interaction between OPN and IL-18 has not been studied in obesity, we investigated whether: (i) their levels were simultaneously elevated in obese individuals; (ii) OPN was associated with IL-18 in obese individuals and (iii) their levels associated with fasting blood glucose (FBG) and BMI.
PBMCs and plasma samples were isolated from 60 individuals including lean as well as overweight and obese individuals. Subcutaneous adipose tissue samples were obtained. OPN and IL-18 were measured by ELISA. OPN and IL-18 mRNA expression was quantified by real time quantitative RT-PCR.
Obese individuals exhibited significantly increased circulating OPN levels as compared with lean individuals (obese 2865±101; lean 1681±116 pg/ml; P<0.0001). IL-18 levels were also high in obese individuals (obese 491±39, lean 301±26 pg/ml; P = 0.0009). OPN and IL-18 expression were simultaneously up-regulated (OPN: 5.4-Fold; IL-18: 8.9-Fold; P<0.05) in PBMCs from obese individuals compared to lean group. Adipose tissue from obese individuals had high expression of OPN (7.3-Fold) and IL-18 (9.6-Fold). Plasma OPN levels correlated positively with FBG levels (r = 0.32, P = 0.02). Similarly, IL-18 correlated positively with FBG levels (r = 0.406, P = 0.0042). Stepwise multiple regression analysis showed an independent association of BMI with OPN and IL-18. Interestingly, OPN levels increased progressively with an increase in IL-18 levels (r = 0.52, P = 0.0004). We also examined the regulatory role of IL-18 in OPN secretion from PBMCs. Neutralizing anti-IL-18Rα mAb reduced OPN secretion.
These findings represent the first observation that plasma, PBMC and adipose tissue OPN and IL-18 are simultaneously increased and correlate with each other in overweight/obese individuals which may trigger the development of obesity-associated insulin resistance. Moreover, these results provide the direct evidence that IL-18 regulates OPN production in PBMCs.
[Show abstract][Hide abstract] ABSTRACT: Background
Expression profile of the toll like receptors (TLRs) on PBMCs is central to the regulation of proinflammatory markers. An imbalance in the TLRs expression may lead to several types of inflammatory disorders. Furthermore, the dynamic regulation of inflammatory activity and associated impaired production of cytokines by peripheral blood mononuclear cells (PBMCs) in obese individulas remain poorly understood. Therefore, we determined the perturbation in TLRs (TLR2 and TLR4), their adaptor proteins (MyD88, IRAK1 and TRAF6) expression in PBMCs/subcutaneous adipose tissue (AT) as well as inflammatory cytokines changes in obese individuals.
mRNA expression levels of TLR2, TLR4, IL-6, TNF-α and adaptor proteins were determined by RT-PCR. TLR2, TLR4 and adaptor proteins expression in AT was determined by immunohistochemistry.
Obese and overweight individuals showed significantly increased expression of TLR2, TLR4 and MyD88 in both PBMCs and AT as compared with lean individuals (P < 0.05). Interestingly, we found a remarkably higher expression of TLRs in obese and overweight individuals with type 2 diabetes (P < 0.05). Increased expression of TLR2, TLR4, MyD88 and IRAK1 correlated with body mass index (BMI) (TLR2: r = 0.91; TLR4: r = 0.88, P <0.0001; MyD88: r = 0.95, P < 0.0001; IRAK1 r = 0.78, P < 0.002). TLRs’ expression was also correlated with fasting blood glucose (FBG) (TLR2: r = 0.61, P < 0.002; TLR4: r = 0.52, P < 0.01) and glycated haemoglobin (HbA1c) ( TLR2: r = 0.44, P <0.03; TLR4: r = 0.48, P < 0.03). Transcript levels of IL-6 and TNF-α were highly elevated in obese subjects compared to lean subjects. There was a strong association of TLRs’ expression in PBMCs with TNF-α (TLR2: r = 0.92; TLR4: r = 0.92; P < 0.0001) and IL-6 (TLR2: r = 0.91, P < 0.0001; TLR4: r = 0.81; P < 0.001). Similarly adaptor proteins were significantly correlated with TNF-α (MyD88: r = 0.9, P < 0.0001; IRAK1: r = 0.86; P < 0.0002) and IL-6 (MyD88: r = 0.91, P < 0.0001; IRAK1: 0.77; P < 0.002).
TLRs and adapter proteins were overexpressed in PBMCs from obese subjects, which correlated with increased expression of TNF-α and IL-6. This association may explain a potential pathophysiological link between obesity and inflammation leading to insulin resistance.
Full-text · Article · Nov 2012 · Journal of Inflammation
[Show abstract][Hide abstract] ABSTRACT: The frequency of metabolic alkalosis among adults with stable severe CF-lung disease is unknown.
Retrospective chart review.
Fourteen CF and 6 COPD (controls) patients were included. FEV1 was similar between the two groups. PaO2 was significantly higher in the COPD (mean ± 2 SD is 72.0 ± 6.8 mmHg,) than in the CF group (56.1 ± 4.1 mmHg). The frequency of metabolic alkalosis in CF patients (12/14, 86%) was significantly greater (p=0.04) than in the COPD group (2/6, 33%). Mixed respiratory acidosis and metabolic alkalosis was evident in 4 CF and 1 COPD patients. Primary metabolic alkalosis was observed in 8 CF and none of the COPD patients. One COPD patient had respiratory and metabolic alkalosis.
Metabolic alkalosis is more frequent in stable patients with CF lung disease than in COPD patients. This might be due to defective CFTR function with abnormal electrolyte transport within the kidney and/ or gastrointestinal tract.
Preview · Article · Jul 2012 · The Open Respiratory Medicine Journal
[Show abstract][Hide abstract] ABSTRACT: The first case of cavitary pulmonary disease caused by Purpureocillium lilacinum is described. The isolate showed atypical microscopic characteristics similar to Acremonium and Fusarium spp., which necessitated molecular identification by sequencing of multiple conserved loci. The patient responded to voriconazole,
reinforcing its therapeutic efficacy for P. lilacinum infections.
Full-text · Article · Feb 2012 · Journal of clinical microbiology
[Show abstract][Hide abstract] ABSTRACT: To develop an Arabic version of the Chronic Respiratory Disease Questionnaire (CRQ) to be known as ArabiCRQ.
We conducted a linguistic validation of the CRQ in the Arabic language. The validation process involved 4 phases, including forward and backward translations, pilot testing, and revision to produce a final version of the ArabiCRQ. Five native Arabic-speaking patients with chronic obstructive pulmonary disease completed the ArabiCRQ both in initial and follow-up visits. Wording was modified according to feedback the participants provided.
Two of the patients' scores changed appreciably, despite ensuring their clinical stability.
The ArabiCRQ may be a valuable tool to assess the health-related quality of life in patients with chronic respiratory diseases.
No preview · Article · May 2011 · Medical Principles and Practice
[Show abstract][Hide abstract] ABSTRACT: Obesity-associated chronic low-grade tissue inflammation is an important
factor in the development of obesity-related pathologies, such
as insulin resistance and type II diabetes. The cause and stimulus of
persistent inflammatory activation in obesity is largely unknown. Toll
like receptors (TLRs) are pattern recognition receptors expressed
abundantly on monocytes and macrophages. TLRs and their activation
lead to the increased transcription of pro-inflammatory cytokines,
chemokines, and reactive oxygen species which may aggravate
pathology in obese individuals. We investigated here whether TLRs
could contribute to the progression and induction of diabetes in obese
individuals. Peripheral blood and abdominal subcutaneous adipose
tissue samples were collected from healthy as well as overweight and
obese individuals, with or without diabetes. The expression of TLR2
and TLR4 was quantified by Immunohistochemistry, Flow Cytometry
and RT-PCR. Proinflammatory cytokines were quantified by ELISA.
Obese and overweight individuals showed significantly increased expression
of TLR2 and TLR4 in monocytes and adipose tissue as
compared with lean individuals (P < 0.05). Interestingly, a remarkably
higher expression of TLRs in obese and overweight individuals with
diabetes type II (P < 0.05) was observed. An increased expression of
TLR2 and TLR4 was correlated with BMI (P < 0.05) but there was no
major difference of TLR5 expression between lean and overweight/
obese individuals. Moreover, a notable association of TLRs with the
blood glucose level was observed (P < 0.05). Our findings suggest that
the elevated expression of TLR-2 and 4, and associated-cytokines in
overweight/obese individuals may play a role in obesity-associated
inflammation and insulin resistance.
[Show abstract][Hide abstract] ABSTRACT: Obesity is associated with adipose tissue inflammation that is involved
in the development of insulin resistance and type 2 diabetes.
Osteopontin (OPN) and IL-18 are known to have potent inflammatory
functions and both participate in a wide range of biological
processes linked to immunological disorders. Since an
interaction between OPN and IL-18 has been suggested in inflammatory
diseases, we investigated whether:
1 Their levels were elevated in obese individuals;
2 Associated with blood glucose and BMI.
PBMCs and plasma samples were isolated from 77 individuals
including lean as well as overweight and obese, with or without
diabetes. Plasma concentrations of OPN and IL-18 were measured by
ELISA. OPN and IL-18 mRNA expression was quantified in PBMCs by
RT-PCR. As compared with lean controls, obese individuals showed
significantly higher plasma concentrations of OPN (lean
2171 ± 203 pg/ml versus obese 2865 ± 101 pg/ml; P < 0.002) and
IL-18 (lean 308 ± 45 versus obese 629 ± 96 pg/ml; P < 0.01). OPN
showed a significant positive correlation with BMI (P < 0.0001) and
blood glucose level (P < 0.03). Similarly, IL-18 positively correlated
with BMI (P < 0.05) and blood glucose level (P < 0.05). Interestingly,
there was a strong association between OPN and IL-18 in obese
individuals. To our knowledge this is the first demonstration showing
that plasma OPN and IL-18 are simultaneously increased in overweight/
obese individuals which may trigger obesity-associated/insulinresistance
development. Further studies are being carried out to dissect
the pathways that involve OPN and IL-18 in obesity.
[Show abstract][Hide abstract] ABSTRACT: Low-grade chronic inflammation is considered as a major determinant
governing obesity and its progression to insulin resistance and type II
diabetes. Recent animal studies suggest that Th1 cells and cytotoxic T
cells are involved in the attraction of proinflammatory adipose tissue
macrophages, which are a major cause of adipose tissue inflammation,
and that Th2 cells are protective from such inflammation. The ST2L
molecule is expressed on the surface of macrophages, monocytes and
Th2 cells. The ligand for ST2L is IL-33. It has been shown that murine
IL-33 acts as a chemoattractant for Th2 cells and induces Th2-associated
cytokine production. In addition, IL-33-treated DCs stimulate
naive CD4+ T cells to produce robust IL-5 and IL-13. Therefore, ST2L/
IL-33 interaction may play a critical role in the induction, maintenance
and recruitment of protective Th2 cells in the adipose tissue. However,
the role of the ST2L/IL-33 pathway in obesity-associated adipose tissue
inflammation and diabetes has not been determined. We aimed in this
study to compare the expression level of ST2L and IL-33 in lean and
obese individuals with and without diabetes.
Plasma, serum, peripheral blood mononuclear cells, and adipose
tissue biopsies were isolated from adult lean and obese subjects with
and without diabetes, and assessed using immunological assays such as
ELISA, Flow Cytometry and Immunohistochemistry. Data on the
expression level of ST2L and IL-33 will be presented. Understanding of
the significance of the ST2L/IL-33 interaction may help in the
prevention of obesity-associated adipose tissue inflammation and
[Show abstract][Hide abstract] ABSTRACT: Obesity is a growing epidemic and is associated with metabolic diseases
such as insulin resistance, hypertension, and cardiovascular disease.
Chronic inflammation is one of the major consequences, which results
in dysfunction of adipose tissue in obese patients. Growing evidence
suggests a role for MMP-9 as a key component in migration of
monocytes/macrophages to adipose tissue. Several studies have showed
increased levels of plasma/serum MMP-9 obtained from obese individuals;
however the source of MMP-9 production has not been
investigated. Therefore, we aimed to identify the sources of MMP-9
production in obese individuals. Plasma concentrations of MMP-9
were measured in samples isolated from 76 individuals by ELISA assay.
mRNA expression of MMP-9 in PBMCs was quantified by RT-PCR
analysis. MMP-9 expression was also determined in the adipose tissues
of these subjects using immunohistochemistry analysis. Overweight
and obese individuals showed a significant increase of MMP-9 expression
in both PBMCs and adipose tissue when compared with lean
individuals (P < 0.05). Interestingly, a remarkable higher expression of
MMP-9 was observed in overweight and obese individuals with type II
diabetes (P < 0.05). These findings indicate that the PBMCs are the
more prone to release and produce MMP-9 in obese individuals.
Further investigations are being carried out to determine the cellular
compartments within the PBMCs and/or adipose tissue that are directly
involved in the modulation and induction of MMP-9 in obese
and diabetic individuals.