Search

Purpose This study paper aims to evaluate the Phytochemical Composition, anti-obesity, anti-antipyretic and analgesic effect of Ephedra alata (Ea) extracts. Design/methodology/approach Obesity was induced in male Wistar rats through a high-fat/fructose diet (HF/FD). Control rats received a standard diet. Findings Results of this study showed that the Ea methanol extract (MEEa) exhibited a prominent selective inhibitory effect against lipase activity (IC50 = 1.29 mg/ml) as compared to water and ethyl acetate extracts (with IC50 = 1.63 and 1.89, respectively). Also, MEEa exert antipyretic and analgesic activities. In high-fat-high-fructose diet rats, the administration of MEEa inhibited lipase activity in the intestine, pancreas and serum by 53%, 40% and 53%, respectively. It was found to significantly decrease body weight by 20% (p = 0.09) and delay the absorption of triglycerides (TG), total cholesterol (TC), LDL-cholesterol (LDL-C) and increase HDL-cholesterol (HDL-C). In addition, MEEa efficiently decreased a-amylase activity in the intestine, pancreas and serum by 43%, 26% and 46%, respectively, and blood glucose level by 35% (p = 0.06). Originality/value To the best of the authors’ knowledge, this study demonstrates for the first time that MEEa are efficient in preventing obesity and hyperglycemia, pain and fever.

Spexin is a novel neuropeptide playing an emerging role in metabolic diseases such as obesity and diabetes via involvement in energy homeostasis and food intake. The present study investigated the effects of obesity and type 2 diabetes (T2D) on circulating levels of spexin and its modulation by physical exercise. Normal-weight (n = 50) and obese adults with and without T2D (n = 69 and n = 66, respectively) were enrolled in the study. A subgroup of obese participants (n = 47) underwent a supervised 3-month exercise programme. Plasma spexin levels were measured by ELISA and correlated with various markers. Plasma spexin levels decreased in obese participants with or without T2D compared with those of normal-weight participants (0.43 ± 0.11, 0.44 ± 0.12 and 0.61 ± 0.23 ng/ml, respectively; P P P 2 max) with a concomitant improvement in metabolic profile. In conclusion, plasma spexin levels may be an indicator of response to physical exercise.

Objective The corticotropin-releasing factor neuropeptides (corticotropin-releasing hormone [CRH] and urocortin [UCN]-1,2,3) and spexin contribute to the regulation of energy balance and inhibit food intake in mammals. However, the status of these neuropeptides in children with overweight has yet to be elucidated. This study investigated the effect of increased body weight on the circulating levels of these neuropeptides. Methods A total of 120 children with a mean age of 12 years were enrolled in the study. Blood samples were collected to assess the circulating levels of neuropeptides and were correlated with various anthropometric, clinical, and metabolic markers. Results Plasma levels of UCNs were altered in children with overweight but less so in those with obesity. Furthermore, the expression pattern of UCN1 was opposite to that of UCN2 and UCN3, which suggests a compensatory effect. However, no significant effect of overweight and obesity was observed on CRH and spexin levels. Finally, UCN3 independently associated with circulating zinc-alpha-2-glycoprotein and UCN2 levels, whereas UCN1 was strongly predicted by TNF alpha levels. Conclusions Significant changes in neuropeptide levels were primarily observed in children with overweight and were attenuated with increased obesity. This suggests the presence of a compensatory mechanism for neuropeptides to curb the progression of obesity.

The corticotropin-releasing hormone (CRH) and urocortins (UCNs) have been implicated in energy homeostasis and the cellular stress response. However, the expression of these neuropeptides in children remains unclear. Therefore, we determined the impact of obesity on their expression in 40 children who were normal weight, overweight, and had obesity. Peripheral blood mononuclear cells (PBMCs) and plasma were used to assess the expression of neuropeptides. THP1 cells were treated with 25 mM glucose and 200 µM palmitate, and gene expression was measured by real-time polymerase chain reaction (RT-PCR). Transcript levels of neuropeptides were decreased in PBMCs from children with increased body mass index as indicated by a significant decrease in UCN1, UCN3, and CRH mRNA in overweight and obese children. UCN3 mRNA expression was strongly correlated with UCN1, UCN2, and CRH. Exposure of THP1 cells to palmitate or a combination of high glucose and palmitate for 24 h increased CRH, UCN2, and UCN3 mRNA expression with concomitant increased levels of inflammatory and endoplasmic reticulum stress markers, suggesting a crosstalk between these neuropeptides and the cellular stress response. The differential impairment of the transcript levels of CRH and UCNs in PBMCs from overweight and obese children highlights their involvement in obesity-related metabolic and cellular stress.

Background. Cardiovascular disease (CVD) risks persist in patients despite the use of conventional treatments. This might be due to chronic inflammation as reflected in epidemiological studies associating circulating low-grade inflammatory markers with CVD recurrent events. Here, we explored this potential link by assessing plasma dual-specificity phosphatase 1 (DUSP1) levels and comparing them to high-sensitivity CRP (hsCRP) and oxidized low-density lipoprotein (oxLDL) levels and their associations to conventional CVD risk factors in confirmed CVD patients.Methods. Human adults with reported CVD (n=207) and controls (n=70) living in Kuwait were used in this study. Anthropometric and classical biochemical parameters were determined. Plasma levels of DUSP1, oxLDL, and hsCRP were measured using human enzyme-linked immunosorbent assay kits.Results. DUSP1 and hsCRP plasma levels and their least square means were higher in CVD cases, while oxLDL plasma levels were lower (p<0.05). Multivariate logistic regression analysis showed that DUSP1 and hsCRP are independently associated with CVD in the studied population, as reflected by 2-fold and 1.5-fold increased risks with increased levels of DUSP1 and hsCRP, respectively. In our study, DUSP1 levels were found to be associated with CVD despite statin treatment and diabetes status (p<0.05), whereas hsCRP mainly correlated with obesity markers.Conclusions. Circulating DUSP1 might be a predictor of chronic subclinical inflammation and residual risk in CVD patients, whereas our data suggest that the association between hsCRP and CVD is largely accounted for adiposity risk factors.

Background The hepatokine fetuin-A is linked to obesity and type 2 diabetes, but its presence and expression in adipose tissue remain unclear. In this study, we aimed to assess the circulating levels of fetuin-A and its expression in subcutaneous adipose tissue (SAT) from diabetic and non-diabetic obese subjects and their modulation by exercise. Methods SAT and blood were obtained from adults obese (diabetic, n=118 and non-diabetic, n=166) before and after a 3-month exercise program (diabetic, n=40 and non-diabetic, n=36, respectively). Plasma fetuin-A was assayed using ELISA. The presence and expression of fetuin-A in SAT, peripheral blood mononuclear cells (PBMCs) and cell lines (3T3-L1, THP-1, HepG2, RAW 264.7) were analysed using confocal microscopy, immunoblotting and qRT-PCR. Results Plasma fetuin-A level did not significantly differ between diabetic and non-diabetic obese subjects. However, when the non-diabetic group was divided into metabolically healthy and unhealthy phenotypes, significantly higher fetuin-A level was observed in the unhealthy sub-group. Circulating fetuin-A was mainly associated with glycaemic markers. In SAT, fetuin-A protein level was significantly higher in the diabetic obese subjects but its mRNA was not detected. Similarly, fetuin-A protein was detected in PBMCs, but its mRNA was not. In line with this, the use of various cell lines and culture media indicated that the presence of fetuin-A in SAT and PBMCs was due to its uptake from circulation rather than its endogenous expression. Finally, physical exercise decreased fetuin-A levels in both plasma and SAT in both groups. Conclusions Fetuin-A levels increased in association with diabetes in SAT but not in circulation in the obese subjects. Moreover, physical exercise decreased fetuin-A level. Fetuin-A potentially acts as a hepatokine taken up by other tissues, such as adipose tissue. Electronic supplementary material The online version of this article (10.1186/s12944-018-0919-x) contains supplementary material, which is available to authorized users.

The aim of this study is to evaluate the anti-obesity, anti-hyperglycaemic, analgesic and antipyretic activities ofGA methanol and water extracts (GAME, GAWE) were administered to high-fat-high-glucose diet (HFFD) rats.This study showed that GAME exhibited the highest antioxidant, anti-α-amylase and anti-lipase activities, with half inhibitory concentration (IC50) values 0.067, 1.05 and 2.97 mg/ml respectively. In HFFD rats, the administration of GAME inhibited lipase activity by 36, 37 and 30% in the intestine, pancreas and serum, respectively, reduced body weight by 17.7% and modulated lipid profile. In addition, administration of GAME to HFFD-rats decreased α-amylase activity, improved glucose level and protected liver function. Furthermore, the administration of GA extracts to rats revealed antipyretic (reduction in writhing by 64%) and analgesic (decrease of temperature by 1.11 °C) activities.This study showed that GA extracts exhibited an anti-obesity, anti-hyperglycaemia, anti-pyretic and analgesic activities.

In vitro, this study showed that unfermented soy milk (USM) and kefir fermented soy milk (FSM) inhibited pancreas lipase with (IC50 = 52.17 and 39.37 μg/mL) and α-amylase activities with (IC50 = 72.60 and 52.71 μg/mL respectively). The most powerful lipase and α -amylase inhibitory activity was observed around 16 h of fermentation. In HFFD rats, the supplement of FSM increased locomotor performance; and decreased intestinal and pancreas lipase activity by 34 and 35% as compared to untreated HDF-rats. This leads to decrease in TC and LDL-c by 24 and 66%; and increase in HDL-c rates of HFFD-rats by 32%, which helped to decrease in body weight by 20%. Moreover administration of FSM to HFFD-rats inhibited intestinal and pancreas α-amylase activity by 26 and 31% as compared to untreated HFFD-rats, and consequently decrease of blood glucose by 36%. In addition, FSM efficiently was protected from hepatic and kidney tissues toxicities.

Epoxide hydrolase 2 (EPHX2) is an emerging therapeutic target in several immunometabolic disorders. EPHX2 metabolizes anti-inflammatory epoxyeicosatrienoic acids into pro-inflammatory diols. The contribution of EPHX2 activity to human obesity remains unexplored. We compared the expression of EPHX2 between lean and obese humans (n = 20 each) in subcutaneous adipose tissue (SAT) and peripheral blood mononuclear cells (PBMCs) using RT-PCR, Western Blot analysis, immunohistochemistry, and confocal microscopy before and after a 3-month physical activity regimen. We also assessed EPHX2 levels during preadipocyte differentiation in humans and mice. EPHX2 mRNA and protein expression were significantly elevated in obese subjects, with concomitant elevated endoplasmic reticulum (ER) stress components (the 78-kDa glucose-regulated protein, GRP78, and the Activating transcription factor 6, ATF6) and inflammatory markers (Tumor necrosis factor-&alpha, TNF&alpha, and Interleukin 6, IL6) as compared to controls (p &lt, 0.05). EPHX2 mRNA levels strongly correlated with adiposity markers. In obese individuals, physical activity attenuated EPHX2 expression levels in both the SAT and PBMCs, with a parallel decrease in ER stress and inflammation markers. EPHX2 expression was also elevated during differentiation of both human primary and 3T3-L1 mouse preadipocytes. Mediators of cellular stress (palmitate, homocysteine, and macrophage culture medium) also increased EPHX2 expression in 3T3-L1 preadipocytes. Our findings suggest that EPHX2 upregulation is linked to ER stress in adiposity and that physical activity may attenuate metabolic stress by reducing EPHX2 expression.

Urocortin3 (UCN3) regulates metabolic functions and is involved in cellular stress response. Although UCN3 is expressed in human adipose tissue, the association of UCN3 with obesity and diabetes remains unclear. This study investigated the effects of Type 2 diabetes (T2D) and increased body weight on the circulatory and subcutaneous adipose tissue (SAT) levels of UCN3 and assessed UCN3 modulation by a regular physical exercise. Normal-weight (n = 37) and overweight adults with and without T2D (n = 98 and n = 107, respectively) were enrolled in the study. A subset of the overweight subjects (n = 39 for each group) underwent a supervised 3-month exercise program combining both moderate intensity aerobic exercise and resistance training with treadmill. UCN3 levels in SAT were measured by immunofluorescence and RT-PCR. Circulatory UCN3 in plasma was assessed by ELISA and was correlated with various clinical and metabolic markers. Our data revealed that plasma UCN3 levels decreased in overweight subjects without T2D compared with normal-weight controls [median; 11.99 (0.78–86.07) and 6.27 (0.64–77.04), respectively; p < 0.001], whereas plasma UCN3 levels increased with concomitant T2D [median; 9.03 (0.77–104.92) p < 0.001]. UCN3 plasma levels were independently associated with glycemic index; fasting plasma glucose and hemoglobin A1c (r = 0.16 and r = 0.20, p < 0.05, respectively) and were significantly different between both overweight, with and without T2D, and normal-weight individuals (OR = 2.11 [1.84–4.11, 95% CI] and OR = 2.12 [1.59–3.10, 95% CI], p < 0.01, respectively). Conversely, the UCN3 patterns observed in SAT were opposite to those in circulation; UCN3 levels were significantly increased with body weight and decreased with T2D. After a 3-month supervised exercise protocol, UCN3 expression showed a significant reduction in SAT of both overweight groups (2.3 and 1.6-fold change; p < 0.01, respectively). In conclusion, UCN levels are differentially dysregulated in obesity in a tissue-dependent manner and can be mitigated by regular moderate physical exercise.

Background and objectives Perturbation of the endoplasmic reticulum (ER) homeostasis has emerged as one of the prominent features of obesity and diabetes. This occurs when the adaptive unfolded protein response (UPR) fails to restore ER function in key metabolic tissues. We previously reported increased inflammation and impaired heat shock response (HSR) in obese human subjects that were restored by physical exercise. Here, we investigated the status of ER stress chaperone; glucose-regulated protein 78 (GRP78) and its downstream UPR pathways in human obese, and their modulation by a supervised 3-month physical exercise. Methods Subcutaneous adipose tissue (SAT) and blood samples were collected from non-diabetic adult human lean (n = 40) and obese (n = 40, at baseline and after 3 months of physical exercise). Transcriptomic profiling was used as a primary screen to identify differentially expressed genes and it was carried out on SAT samples using the UPR RT 2 Profiler PCR Array. Conventional RT-PCR, immunohistochemistry, immunofluorescence, Western blot and ELISA were used to validate the transcriptomic data. Correlation analyses with the physical, clinical and biochemical outcomes were performed using Pearson's rank correlation coefficient. Results Levels of GRP78 and its three downstream UPR arms; activating transcription factor-6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were increased in obese subjects. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects which correlated negatively with maximum oxygen uptake (V O2 Max ) but positively with high-sensitivity C-reactive protein (hsCRP) and obesity indicators such as BMI, percentage body fat (PBF) and waist circumference. GRP78 increased secretion in obese was further confirmed in vitro using 3T3-L1 preadipocyte cells under ER stress. Finally, we showed that physical exercise significantly attenuated the expression and release of GRP78 with a concomitant reduction in the phosphorylation of IRE1α and eukaryotic initiation factor-2α (eIF2α). Conclusion Our results suggest that physical exercise alleviates ER stress in human obese through attenuation of GRP78 signaling network.

Heat shock protein 60 (HSP60) is a key protein in the crosstalk between cellular stress and inflammation. However, the status of HSP60 in diabetes and obesity is unclear. In the present study, we investigated the hypothesis that HSP60 expression levels in the adipose tissue of human obese adults with and without diabetes are different and physical exercise might affect these levels. Subcutaneous adipose tissue (SAT) and blood samples were collected from obese adults with and without diabetes (n = 138 and n = 92, respectively, at baseline; n = 43 for both groups after 3 months of physical exercise). Conventional RT-PCR, immunohistochemistry, immunofluorescence, and ELISA were used to assess the expression and secretion of HSP60. Compared with obese adults without diabetes, HSP60 mRNA and protein levels were decreased in SAT in diabetic obese together with increased inflammatory marker expression and glycemic levels but lower VO2 Max. More interestingly, a 3-month physical exercise differentially affected HSP60 expression and the heat shock response but attenuated inflammation in both groups, as reflected by decreased endogenous levels of IL-6 and TNF-α. Indeed, HSP60 expression levels in SAT were significantly increased by exercise in the diabetes group, whereas they were decreased in the non-diabetes group. These results were further confirmed using immunofluorescence microscopy and anti-HSP60 antibody in SAT. Exercise had only marginal effects on HSP60 secretion and HSP60 autoantibody levels in plasma in both obese with and without diabetes. Physical exercise differentially alleviates cellular stress in obese adults with and without diabetes despite concomitant attenuation of the inflammatory response.

BackgroundObesity and its co-morbidities are characterized by a chronic low-grade inflammatory state, uncontrolled expression of metabolic measurements and dis-regulation of various forms of stress response. However, the contribution and correlation of inflammation, metabolism and stress responses to the disease are not fully elucidated. In this paper a cross-sectional case study was conducted on clinical data comprising 117 human male and female subjects with and without type 2 diabetes (T2D). Characteristics such as anthropometric, clinical and bio-chemical measurements were collected.MethodsAssociation of these variables with T2D and BMI were assessed using penalized hierarchical linear and logistic regression. In particular, elastic net, hdi and glinternet were used as regularization models to distinguish between cases and controls. Differential network analysis using closed-form approach was performed to identify pairwise-interaction of variables that influence prediction of the phenotype.ResultsFor the 117 participants, physical variables such as PBF, HDL and TBW had absolute coefficients 0.75, 0.65 and 0.34 using the glinternet approach, biochemical variables such as MIP, ROS and RANTES were identified as determinants of obesity with some interaction between inflammatory markers such as IL4, IL-6, MIP, CSF, Eotaxin and ROS. Diabetes was associated with a significant increase in thiobarbituric acid reactive substances (TBARS) which are considered as an index of endogenous lipid peroxidation and an increase in two inflammatory markers, MIP-1 and RANTES. Furthermore, we obtained 13 pairwise effects. The pairwise effects include pairs from and within physical, clinical and biochemical features, in particular metabolic, inflammatory, and oxidative stress markers.ConclusionsWe showcase that markers of oxidative stress (derived from lipid peroxidation) such as MIP-1 and RANTES participate in the pathogenesis of diseases such as diabetes and obesity in the Arab population.

Background: Obesity and its co-morbidities are characterized by a chronic low-grade in amatory state, uncontrolled expression of metabolic measurements and dis-regulation of various forms of stress response. However, the contribution and correlation of in ammation, metabolism and stress responses to the disease are not fully elucidated. In this paper a cross-sectional case study was conducted on clinical data comprising 117 human male and female subjects with and without Type 2 Diabetes (T2D). Characteristics such as anthropometric, clinical and biochemical measurements were collected. Methods: Association of these variables with T2D and BMI were assessed using penalized hierarchical linear and logistic regression. In particular, elastic net, hdi and glinternet were used as regularization models to distinguish between cases and controls. Differential network analysis using closed-form approach was performed to identify pairwise-interaction of variables that influence prediction of the phenotype. Results: For the 117 participants, physical variables such as PBF, HDL and TBW had absolute coefficients 0.75, 0.65 and 0.34 using the glinternet approach, biochemical variables such as MIP, ROS and RANTES were identified as determinants of obesity with some interaction between inflammatory markers such as IL-4, IL-6, MIP, CSF, Eotaxin and ROS. Diabetes was associated with a significant increase in Thiobarbituric Acid Reactive Substances (TBARS) which are considered as an index of endogenous lipid peroxidation and an increase in two inflammatory markers, MIP-1 and RANTES. Furthermore, we obtained 13 pairwise effects. The pairwise effects include pairs from and within physical, clinical and biochemical features, in particular metabolic, inflammatory, and oxidative stress markers. Conclusion: We showcase those markers of oxidative stress (derived from lipid peroxidation) such as MIP-1 and RANTES participate in the pathogenesis of diseases such as diabetes and obesity in the Arab population.

Heat shock response (HSR) is an essential host-defense mechanism that is dysregulated in obesity-induced insulin resistance and type 2 diabetes (T2D). Our recent data demonstrated that DNAJB3 was downregulated in obese human subjects and showed negative correlation with inflammatory markers. Nevertheless, DNAJB3 expression pattern in diabetic subjects and its mode of action are not yet known. In this study, we showed reduction in DNAJB3 transcript and protein levels in PBMC and subcutaneous adipose tissue of obese T2D compared to obese non-diabetic subjects. Overexpression of DNAJB3 in HEK293 and 3T3-L1 cells reduced JNK, IRS-1 Ser-307 phosphorylation and enhanced Tyr-612 phosphorylation suggesting an improvement in IRS-1 signaling. Furthermore, DNAJB3 mediated the PI3K/AKT pathway activation through increasing AKT and AS160 phosphorylation. AS160 mediates the mobilization of GLUT4 transporter to the cell membrane and thereby improves glucose uptake. Using pre-adipocytes cells we showed that DNAJB3 overexpression caused a significant increase in the glucose uptake, possibly through its phosphorylation of AS160. In summary, our results shed the light on the possible role of DNAJB3 in improving insulin sensitivity and glucose uptake through JNK repression and suggest that DNAJB3 could be a potential target for therapeutic treatment of obesity-induced insulin resistance.

Background. The impact of gender difference on the association between metabolic stress and cardiovascular disease (CVD) remains unclear. We have investigated, for the first time, the gender effect on the oxidative and inflammatory stress responses and assessed their correlation with classical cardiometabolites in Arab population.Methods. A total of 378 adult Arab participants (193 females) were enrolled in this cross-sectional study. Plasma levels of CRP, IL-6, IL-8, TNF-α, ROS, TBARs, and PON1 were measured and correlated with anthropometric and cardiometabolite parameters of the study population.Results. Compared to females, males had significantly higher FBG, HbA1c, TG, and blood pressure but lower BMI, TC, and HDL (P P α(P α, IL-6, and ROS were associated with central obesity but not general obesity.Conclusion. Inflammation and oxidative stress contribution to CVD risk in Arab population linked to gender and this risk is better reflected by central obesity. Arab females might be at risk of CVD complications due to increased oxidative stress.

Objective ANGPTL7 is a member of the Angiopoietin-like (ANGPTL) protein family that is composed of eight proteins (1-8). Increasing evidence is associating ANGPTL proteins to obesity and insulin resistance. The biological role of ANGPTL7 is yet to be understood except for a recently proposed role in the pathophysiology of glaucoma. This study was designed to shed light on the function of ANGPTL7 in obesity and its modulation by physical exercise as well as its potential association with lipid profile. Methods A total of 144 subjects were enrolled in this study and finished three months of physical exercise. The participants were classified based on their BMI, 82 subjects were non-obese and 62 obese. ANGPTL7 levels in plasma and adipose tissue were measured by ELISA, RT-PCR and immunohistochemistry. Results In this study, we showed that ANGPTL7 level was increased in the plasma of obese subjects (1249.05± 130.39 pg/mL) as compared to non-obese (930.34 ± 87.27 pg/mL) (p-Value = 0.032). ANGPTL7 Gene and protein expression levels in adipose tissue also showed over two fold increase. Physical exercise reduced circulating level of ANGPTL7 in the obese subjects to 740.98± 127.18 pg/mL, (p-Value = 0.007). ANGPTL7 expression in adipose tissue was also reduced after exercise. Finally, ANGPTL7 circulating level showed significant association with TG level in the obese subjects (R2 = 0.183, p-Value = 0.03). Conclusion In conclusion, our data shows for the first time that obesity increases the level of ANGPTL7 in both plasma and adipose tissue. Increased expression of ANGPTL7 might play a minor role in the regulation of TG level in obese subjects either directly or through interaction with other ANGPTL protein members. Physical exercise reduced the level of ANGPTL7 highlighting the potential for targeting this protein as a therapeutic target for regulating dyslipidemia.

Chronic low-grade inflammation and dysregulation of the stress defense system are cardinal features of obesity, a major risk factor for the development of insulin resistance and diabetes. Dual-specificity protein phosphatase 1 (DUSP1), known also as MAP kinase phosphatase 1 (MKP1), 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 nondiabetic human subjects using subcutaneous adipose tissue (SAT) and peripheral blood mononuclear cells (PBMCs). The levels of DUSP1 mRNA and protein were significantly increased in obese subjects with concomitant decrease in the phosphorylation of p38 MAPK (p-p38 MAPK) and PGC-1α and an increase in the levels of phospho-JNK (p-JNK) and phospho-ERK (p-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 V̇o2max and high-density lipoprotein ( P < 0.05). The observation that DUSP1 was overexpressed in obese subjects prompted us to investigate whether physical exercise could reduce its expression. In this study, we report for the first time that physical exercise significantly attenuated the expression of DUSP1 in both the SAT and PBMCs, with a parallel increase in the expression of PGC-1α and a reduction in the levels of p-JNK and p-ERK along with attenuated inflammatory response. Collectively, our data suggest that DUSP1 upregulation is strongly linked to adiposity and that 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.

Chronic low-grade inflammation and uncontrolled metabolic stress response are cardinal features of obesity; a major risk factor for the development 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

Ghrelin is a stomach produced hormone that has been shown to have protective role against development of CVD which is a leading cause of death in the Arab world. The objective of this study is to examine the gender difference in association between traditional CVD risk factors and plasma ghrelin among Arabs. 359 Arab residents in Kuwait participated in a cross-sectional survey (≥20 years old): 191 were females and 168 were males. Plasma level of ghrelin was assessed using Luminex-based assay. Ghrelin levels were significantly higher in females (935 ± 78 pg/mL) than males (763 ± 65 pg/mL) (P=0.0007). Females showed inverse association with WC (r=-0.23,P=0.001) and HbA1C (r=-0.19,P=0.0102) as well as SBP (r=-0.15,P=0.0383) and DBP (r=-0.16,P=0.0230), respectively. Higher levels of ghrelin were shown to associate with increased insulin resistance, as measured by HOMAIR, in male Arab subjects (P-trend = 0.0202) but not in females. In this study we show that higher ghrelin level was negatively associated with measures of obesity, HbA1C, and blood pressure in females and positively associated with increased insulin resistance in Arab males.

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.

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.

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. Methods 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. Results 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

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.

Association of obesity with down-regulation of heat shock protein 40 expression and evidence that exercise retrieves its normal expression Jehad Abubakr, Mohamed Abu-Farha, Monira Al-Arouj, Fahad Al-Ghimlas, Irina Al-Khairi, Dalal Al-Mudhaf, Engin Baturcam, Abdullah Bennakhi, Preethi Cherian, Maha Hammad, Jeena John, Sina Kavalakatt, Abdelkrim Khadir, Ali Tiss, Samia Warsame, Said Dermime, Mohammed Dehbi

Meeting abstracts Obesity is a major risk factor for metabolic diseases and cancer. Lifestyle interventions in obesity reduce the risk for cancer. Aberrant regulation of dual specificity protein phosphatase 1 (DUSP1) was linked to obesity and cancer representing an attractive therapeutic target and