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The NLRP3-IL-1β pathway plays an important role in adipose tissue (AT)-induced inflammation and the development of obesity-associated comorbidities. We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix (ECM) remodeling. Samples obtained from 98 subjects were used in a case-control study. The expression of different components of the inflammasome as well as their main effectors and inflammation- and ECM remodeling-related genes were analyzed. The impact of blocking NLRP3 using siRNA in lipopolysaccharide (LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated. We demonstrated that obesity (P < 0.01), obesity-associated T2D (P < 0.01) and NAFLD (P < 0.05) increased the expression of different components of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT. We also found that obese patients with T2D exhibited increased (P < 0.05) hepatic gene expression levels of NLRP3, IL1B and IL18. We showed that NLRP3, but not NLRP1, is regulated by inflammation and hypoxia in visceral adipocytes. We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked (P < 0.01) LPS-induced inflammation by downregulating the mRNA levels of CCL2, IL1B, IL6, IL8, S100A8, S100A9, TLR4 and TNF as well as inhibiting (P < 0.01) the secretion of IL1-β into the culture medium. Furthermore, blocking NLRP3 attenuated (P < 0.01) the LPS-induced expression of important molecules involved in AT fibrosis (COL1A1, COL4A3, COL6A3 and MMP2). These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.

Objective: Kallistatin plays an important role in the inhibition of inflammation, oxidative stress, fibrosis and angiogenesis. We aimed to determine the impact of kallistatin on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and oxidative stress., Methods: Samples obtained from 95 subjects were used in a case-control study. Circulating concentrations and expression levels of kallistatin as well as key inflammation, oxidative stress and extracellular matrix remodelling-related genes were analyzed. Circulating kallistatin concentrations were measured before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB). The impact of kallistatin on lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-α-mediated inflammatory as well as oxidative stress signalling pathways was evaluated., Results: We show that the reduced (P < 0.00001) circulating levels of kallistatin in obese patients increased (P < 0.00001) after RYGB. Moreover, gene expression levels of SERPINA4, the gene coding for kallistatin, were downregulated (P < 0.01) in the liver from obese subjects with non-alcoholic fatty liver disease. Additionally, we revealed that kallistatin reduced (P < 0.05) the expression of inflammation-related genes (CCL2, IL1B, IL6, IL8, TNFA, TGFB) and, conversely, upregulated (P < 0.05) mRNA levels of ADIPOQ and KLF4 in human adipocytes in culture. Kallistatin inhibited (P < 0.05) LPS- and TNF-α-induced inflammation in human adipocytes via downregulating the expression and secretion of key inflammatory markers. Furthermore, kallistatin also blocked (P < 0.05) TNF-α-mediated lipid peroxidation as well as NOX2 and HIF1A expression while stimulating (P < 0.05) the expression of SIRT1 and FOXO1., Conclusions: These findings provide, for the first time, evidence of a novel role of kallistatin in obesity and its associated comorbidities by limiting adipose tissue inflammation and oxidative stress., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Interleukin (IL)-32 is a recently described cytokine involved in the regulation of inflammation. We aimed to explore whether IL-32 could function as an inflammatory and angiogenic factor in human obesity and obesity-associated type 2 diabetes. Samples obtained from 90 subjects were used in the study. Obese patients exhibited higher expression levels of IL-32 in visceral adipose tissue (AT) as well as in subcutaneous AT and peripheral blood mononuclear cells. IL32 was mainly expressed by stromovascular fraction cells, and its expression was significantly enhanced by inflammatory stimuli and hypoxia, whereas no changes were found after the incubation with anti-inflammatory cytokines. The addition of exogenous IL-32 induced the expression of inflammation and extracellular matrix-related genes in human adipocyte cultures, and IL32-silenced adipocytes showed a downregulation of inflammatory genes. Furthermore, adipocyte-conditioned media obtained from obese patients increased IL32 gene expression in human monocyte cultures, whereas the adipocyte-conditioned media from lean volunteers had no effect on IL32 mRNA levels. These findings provide evidence, for the first time, about the inflammatory and remodeling properties of IL-32 in AT, implicating this cytokine in obesity-associated comorbidities., (© 2016 by the American Diabetes Association.)

Objective: To assess the predictive capacity of a recently described equation that we have termed CUN-BAE (Clínica Universidad de Navarra-Body Adiposity Estimator) based on BMI, sex, and age for estimating body fat percentage (BF%) and to study its clinical usefulness., Research Design and Methods: We conducted a comparison study of the developed equation with many other anthropometric indices regarding its correlation with actual BF% in a large cohort of 6,510 white subjects from both sexes (67% female) representing a wide range of ages (18-80 years) and adiposity. Additionally, a validation study in a separate cohort (n = 1,149) and a further analysis of the clinical usefulness of this prediction equation regarding its association with cardiometabolic risk factors (n = 634) was carried out., Results: The mean BF% in the cohort of 6,510 subjects determined by air displacement plethysmography was 39.9 ± 10.1%, and the mean BF% estimated by the CUN-BAE was 39.3 ± 8.9% (SE of the estimate, 4.66%). In this group, BF% calculated with the CUN-BAE showed the highest correlation with actual BF% (r = 0.89, P < 0.000001) compared with other anthropometric measures or BF% estimators. Similar agreement was found in the validation sample. Moreover, BF% estimated by the CUN-BAE exhibits, in general, better correlations with cardiometabolic risk factors than BMI as well as waist circumference in the subset of 634 subjects., Conclusions: CUN-BAE is an easy-to-apply predictive equation that may be used as a first screening tool in clinical practice. Furthermore, our equation may be a good tool for identifying patients at cardiovascular and type 2 diabetes risk.

Objective: Caveolin-1 (CAV-1) plays important roles in many aspects of cellular biology, including vesicular transport, cholesterol homeostasis and signal transduction. The aim of the present study was to explore gene expression levels of CAV-1 in human adipose tissue in obesity and obesity-associated type 2 diabetes mellitus (T2DM) and to analyse its potential implication in the inflammatory state associated with obesity., Design and Methods: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) obtained from 15 females were used in the study. Patients were classified as lean (BMI 20.8 +/- 1.0 kg/m(2)) or obese (BMI 50.5 +/- 2.6 kg/m(2)). The obese group was further subclassified as normoglycaemic (NG) or patients with T2DM. Anthropometric measurements as well as circulating metabolites, hormones and adipokines were determined. Real-time polymerase chain reaction (PCR) analyses were performed to quantify transcript levels of CAV-1 and monocyte chemoattractant protein (MCP-1)., Results: The presence of CAV-1 protein was detected in VAT and SAT by immunohistochemistry. Both obese NG and with T2DM patients exhibited significantly higher CAV-1 expression levels in VAT and SAT compared with lean subjects (P < 0.05). No differences between obese NG and T2DM patients were observed in VAT. However, obese T2DM patients were found to have higher CAV-1 expression levels in SAT (P < 0.05) compared with obese NG patients. A significant correlation was found between CAV-1 mRNA expression levels in VAT and different circulating inflammatory markers such as sialic acid (SA) (P < 0.001) and fibrinogen (P < 0.001) as well as with MCP1 mRNA expression (P < 0.05)., Conclusion: Our findings show for the first time the upregulation of mRNA CAV-1 expression levels in VAT and SAT of obese NG and obese T2DM patients compared with lean controls, suggesting a role for CAV-1 in obesity and T2DM development. The association with different inflammatory markers further suggests an implication of CAV-1 in the low-grade inflammation accompanying obesity.

Background: Obesity is considered a state of low-grade chronic inflammation, which may favor the development of cardiovascular diseases. Serum amyloid A (SAA) is an acute phase protein synthesized in response to infection, inflammation, injury, and stress. The aim of the present study was to compare the circulating concentrations of SAA and the mRNA expression in omental adipose tissue between lean and obese individuals and to analyze the effect of weight loss after gastric bypass., Methods: 16 lean volunteers (BMI 20.5 +/- 0.6 kg/m2) and 24 obese patients (BMI 47.0 +/- 1.2 kg/m2) were included in the study. Serum concentrations of SAA were measured by ELISA. In addition, the concentrations of SAA in 18 morbidly obese patients (7 male/11 female; BMI 44.6 +/- 1.9 kg/m2) were measured before and after weight loss following Roux-en-Y gastric bypass (RYGBP). SAA expression in omental adipose tissue was quantified by RT-PCR in biopsies from obese patients undergoing RYGBP and from age-matched lean individuals subjected to Nissen fundoplication., Results: Obese patients exhibited significantly increased circulating SAA concentrations (6.6 +/- 0.5 vs 39.3 +/- 9.1 microg/ml; P<0.01) compared to lean subjects. A significant positive correlation was found between logSAA and body fat (r=0.631, P<0.0001). Obese patients showed significantly increased (P<0.05) mRNA expression of SAA in omental adipose tissue compared to lean subjects. Weight loss significantly decreased SAA concentrations after RYGBP (final BMI 28.5 +/- 0.9 kg/m2, P<0.0001 vs initial) from 47.5 +/- 14.5 to 15.7 +/- 2.9 microg/ml (P<0.05)., Conclusion: It can be concluded that serum SAA and mRNA expression of SAA in omental adipose tissue are increased in obese patients contributing to the obesity-associated cardiovascular disease risk. Moreover, weight loss reduces SAA concentrations, which may contribute to the beneficial effects accompanying weight reduction.

Context Climate change and global warming have been hypothesized to influence the increased prevalence of obesity worldwide. However, the evidence is scarce. Objective We aimed to investigate how outside temperature might affect adipose tissue physiology and metabolic traits. Methods The expression of genes involved in thermogenesis/browning and adipogenesis were evaluated (through quantitative polymerase chain reaction) in the subcutaneous adipose tissue (SAT) from 1083 individuals recruited in 5 different regions of Spain (3 in the North and 2 in the South). Plasma biochemical variables and adiponectin (enzyme-linked immunosorbent assay) were collected through standardized protocols. Mean environmental outdoor temperatures were obtained from the National Agency of Meteorology. Univariate, multivariate, and artificial intelligence analyses (Boruta algorithm) were performed. Results The SAT expression of genes associated with browning (UCP1 , PRDM16 , and CIDEA) and ADIPOQ were significantly and negatively associated with minimum, average, and maximum temperatures. The latter temperatures were also negatively associated with the expression of genes involved in adipogenesis (FASN , SLC2A4 , and PLIN1). Decreased SAT expression of UCP1 and ADIPOQ messenger RNA and circulating adiponectin were observed with increasing temperatures in all individuals as a whole and within participants with obesity in univariate, multivariate, and artificial intelligence analyses. The differences remained statistically significant in individuals without type 2 diabetes and in samples collected during winter. Conclusion Decreased adipose tissue expression of genes involved in browning and adiponectin with increased environmental temperatures were observed. Given the North-South gradient of obesity prevalence in these same regions, the present observations could have implications for the relationship of the obesity pandemic with global warming. [ABSTRACT FROM AUTHOR]

Simple Summary: Netrin-1 (NTN-1) regulates obesity-associated low-grade inflammation, being also involved in the control of cell migration and proliferation. We aim to study whether excess visceral adipose tissue in patients with obesity and colon cancer is associated with increased NTN1 and the expression levels of its main receptors, promoting an inflammatory microenvironment that favours colon cancer development. Increased expression levels of NTN1 and its receptor NEO1 in the visceral adipose tissue from patients with obesity and colon cancer together with elevated DCC and UNC5B mRNA levels in patients with colon cancer were found. Moreover, the treatment of colorectal cancer cells with NTN-1 and with the adipocyte-derived secretome obtained from patients with obesity increased the migration of colorectal cancer cells. These results suggest that NTN-1 plays an important role in obesity-associated colon cancer development. Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells. [ABSTRACT FROM AUTHOR]

Biomechanical properties of adipose tissue (AT) are closely involved in the development of obesity-associated comorbidities. Bariatric surgery (BS) constitutes the most effective option for a sustained weight loss in addition to improving obesity-associated metabolic diseases including type 2 diabetes (T2D). We aimed to determine the impact of weight loss achieved by BS and caloric restriction (CR) on the biomechanical properties of AT. BS but not CR changed the biomechanical properties of epididymal white AT (EWAT) from a diet-induced obesity rat model, which were associated with metabolic improvements. We found decreased gene expression levels of collagens and Lox together with increased elastin and Mmps mRNA levels in EWAT after BS, which were also associated with the biomechanical properties. Moreover, an increased blood vessel density was observed in EWAT after surgery, confirmed by an upregulation of Acta2 and Antxr1 gene expression levels, which was also correlated with the biomechanical properties. Visceral AT from patients with obesity showed increased stiffness after tensile tests compared to the EWAT from the animal model. This study uncovers new insights into EWAT adaptation after BS with decreased collagen crosslink and synthesis as well as an increased degradation together with enhanced blood vessel density providing, simultaneously, higher stiffness and more ductility. Biomechanical properties of the adipose tissue (AT) are closely involved in the development of obesity-associated comorbidities. In this study, we show for the first time that biomechanical properties of AT determined by E , UTS and strain at UTS are decreased in obesity, being increased after bariatric surgery by the promotion of ECM remodelling and neovascularization. Moreover, these changes in biomechanical properties are associated with improvements in metabolic homeostasis. Consistently, a better characterization of the plasticity and biomechanical properties of the AT after bariatric surgery opens up a new field for the development of innovative strategies for the reduction of fibrosis and inflammation in AT as well as to better understand obesity and its associated comorbidities. [Display omitted] [ABSTRACT FROM AUTHOR]

Interleukin (IL)-36 is a recently described cytokine with well-known functions in the regulation of multiple inflammatory diseases. Since no data exists on how this cytokine regulates adipose tissue (AT) homeostasis, we aimed to explore the function of a specific isoform, IL-36γ, an agonist, in human obesity and obesity-associated type 2 diabetes as well as in AT inflammation and fibrosis. Plasma IL-36γ was measured in 91 participants in a case-control study and the effect of weight loss was evaluated in 31 patients with severe obesity undergoing bariatric surgery. Gene expression levels of IL36G and its receptor were analyzed in relevant human metabolic tissues. The effect of inflammatory factors and IL-36γ was determined in vitro in human adipocytes and macrophages. We found, for the first time, that the increased (P <0.05) circulating levels of IL-36γ in patients with obesity decreased (P <0.001) after weight and fat loss achieved by Roux-en-Y gastric bypass and that gene expression levels of IL36G were upregulated in the visceral AT (P <0.05) and in the peripheral blood mononuclear cells (P <0.01) from patients with obesity. We also demonstrated increased (P <0.05) expression levels of Il36g in the epididymal AT from diet-induced obese mice. IL36G was significantly enhanced (P <0.001) by LPS in human adipocytes and monocyte-derived macrophages, while no changes were found after the incubation with anti-inflammatory cytokines. The addition of IL-36γ for 24 h strongly induced (P <0.01) its own expression as well as key inflammatory and chemoattractant factors with no changes in genes associated with fibrosis. Furthermore, adipocyte-conditioned media obtained from patients with obesity increased (P <0.01) the release of IL-36γ and the expression (P <0.05) of cathepsin G (CTSG) in monocyte-derived macrophages. These findings provide, for the first time, evidence about the properties of IL-36γ in the regulation of AT-chronic inflammation, emerging as a link between AT biology and the obesity-associated comorbidities. [ABSTRACT FROM AUTHOR]

Background: Excess adiposity leads to a dysfunctional adipose tissue that contributes to the development of obesity-associated comorbidities such as type 2 diabetes (T2D). Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring antagonist of the IL-1 receptor with anti-inflammatory properties. The aim of the present study was to compare the circulating concentrations of IL-1RA and its mRNA expression in visceral adipose tissue (VAT) in subjects with normal weight (NW), obesity with normoglycemia (OB-NG), or obesity with impaired glucose tolerance or T2D (OB-IGT&T2D) and to analyze the effect of changes in body fat percentage (BF%) on IL-1RA levels. Methods: Serum concentrations of IL-1RA were measured in 156 volunteers. Expression of IL1RN mRNA in VAT obtained from 36 individuals was determined. In addition, the concentrations of IL-1RA were measured before and after weight gain as well as weight loss following a dietetic program or Roux-en-Y gastric bypass (RYGB). Results: Serum levels of IL-1RA were significantly increased in individuals with obesity, being further increased in the OB-IGT&T2D group (NW 440 ± 316, OB-NG 899 ± 562, OB-IGT&T2D 1265 ± 739 pg/mL; P< 0.001) and associated with markers of inflammation and fatty liver. IL1RN mRNA expression in VAT was significantly increased in the OB-IGT&T2D group and correlated in the global cohort with the mRNA expression of SPP1, CCL2, CD68, and MMP9. Levels of IL-1RA were not modified after modest changes in BF%, but RYGB-induced weight loss significantly decreased IL-1RA concentrations from 1233 ± 1009 to 660 ± 538 pg/mL (P< 0.001). Conclusion: Serum IL-1RA concentrations are increased in patients with obesity being further elevated in obesity-associated IGT and T2D in association with markers of adipose tissue dysfunction. The mRNA expression of IL1RN is markedly increased in VAT of subjects with obesity and T2D in relation with genes involved in macrophage recruitment, inflammation and matrix remodeling. Serum IL-1RA concentrations are reduced when a notable amount of BF% is loss. Measurement of IL-1RA is an excellent biomarker of adipose tissue dysfunction in obesity-associated metabolic alterations. [ABSTRACT FROM AUTHOR]

Background: Inflammasomes maintain tissue homeostasis and their altered regulation in the colon, and the adipose tissue (AT) leads to chronic activation of inflammatory pathways promoting colon cancer (CC) development. We aimed to analyze the potential involvement of inflammasomes in obesity-associated CC. Methods: Ninety-nine volunteers [61 with obesity (OB) and 38 normoponderal (NP)] further subclassified according to the approved protocol for the diagnosis of CC (58 without CC and 41 with CC) were included in the case–control study. Results: CC (P< 0.01) and obesity (P< 0.01) were accompanied by increased mRNA levels of NLRP3, NLRP6, ASC, IL1B and NOD2 in VAT. Contrarily, patients with CC exhibited a downregulation of NLRP6 and IL18 in their colon. Additionally, we revealed that the decreased Nlrp1 (P< 0.05), Nlrp3 (P< 0.01) and Nlrp6 (P< 0.01) mRNA levels in the colon from obese rats significantly increase (P< 0.05) after caloric restriction. Adipocyte-conditioned media obtained from subjects with obesity reduced (P< 0.01) the mRNA of NLRP3 as well as molecules involved in maintaining the intestinal integrity (MUC2, CLDN1 and TJP1) and the anti-inflammatory factors FGF21, KLF4, and IL33 and in HT-29 cells. We also found that the knockdown of NLRP6 in HT-29 cells significantly upregulated (P< 0.05) the mRNA of NLRP1 and NLRP3 and inhibited (P< 0.05) the expression levels of MUC2. Finally, we showed that the incubation of HT-29 with Akkermansia muciniphila influence (P< 0.05) the inflammasome expression profile as well as intestinal integrity-related genes and aberrant inflammation. Conclusions: These findings provide evidence that the downregulated levels of NLRP6 and IL18 in the colon from patients with CC may be responsible for a reduced intestinal-barrier integrity, triggering local inflammation, which in turn acts on the dysfunctional AT in obesity, increasing the expression of different inflammasome components and flaring up a vicious cycle of uncontrollable inflammatory cascades that favours a pro-tumorigenic microenvironment. [ABSTRACT FROM AUTHOR]

Background: Excess adipose tissue represents a major risk factor for the development of colon cancer with inflammation and extracellular matrix (ECM) remodeling being proposed as plausible mechanisms. The aim of this study was to investigate whether obesity can influence circulating levels of inflammation-related extracellular matrix proteins in patients with colon cancer (CC), promoting a microenvironment favorable for tumor growth. Methods: Serum samples obtained from 79 subjects [26 lean (LN) and 53 obese (OB)] were used in the study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (44 without CC and 35 with CC). Anthropometric measurements as well as circulating metabolites and hormones were determined. Circulating concentrations of the ECM proteins osteopontin (OPN), chitinase-3-like protein 1 (YKL-40), tenascin C (TNC) and lipocalin-2 (LCN-2) were determined by ELISA. Results: Significant differences in circulating OPN, YKL-40 and TNC concentrations between the experimental groups were observed, being significantly increased due to obesity (P<0.01) and colon cancer (P<0.05). LCN-2 levels were affected by obesity (P<0.05), but no differences were detected regarding the presence or not of CC. A positive association (P<0.05) with different inflammatory markers was also detected. Conclusions: To our knowledge, we herein show for the first time that obese patients with CC exhibit increased circulating levels of OPN, YKL-40 and TNC providing further evidence for the influence of obesity on CC development via ECM proteins, representing promising diagnostic biomarkers or target molecules for therapeutics. [ABSTRACT FROM AUTHOR]

Objective: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Methods: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Results: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 α3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development. [ABSTRACT FROM AUTHOR]

Compelling evidence suggests that dermatopontin (DPT) regulates collagen and fibronectin fibril formation, the induction of cell adhesion and the prompting of wound healing. We aimed to evaluate the role of DPT on obesity and its associated metabolic alterations as well as its impact in visceral adipose tissue (VAT) inflammation and extracellular matrix (ECM) remodelling. Samples obtained from 54 subjects were used in a case-control study. Circulating and VAT expression levels of DPT as well as key ECM remodelling- and inflammation-related genes were analysed. The effect of pro- and anti-inflammatory mediators on the transcript levels of DPT in visceral adipocytes was explored. The impact of DPT on ECM remodelling and inflammation pathways was also evaluated in cultured adipocytes. We show that obesity and obesity-associated type 2 diabetes (T2D) increased (p < 0.05) circulating levels of DPT. In this line, DPT mRNA in VAT was increased (p < 0.05) in obese patients with and without T2D. Gene expression levels of DPT were enhanced (p < 0.05) in human visceral adipocytes after the treatment with lipopolysaccharide, tumour growth factor (TGF)-β and palmitic acid, whereas a downregulation (p < 0.05) was detected after the stimulation with interleukin (IL)-4 and IL-13, critical cytokines mediating anti-inflammatory pathways. Additionally, we revealed that DPT increased (p < 0.05) the expression of ECM- (COL6A3, ELN, MMP9, TNMD) and inflammation-related factors (IL6, IL8, TNF) in human visceral adipocytes. These findings provide, for the first time, evidence of a novel role of DPT in obesity and its associated comorbidities by influencing AT remodelling and inflammation. [ABSTRACT FROM AUTHOR]

Objective: Glucagon-like peptide (GLP)-1 has been proposed as a key candidate in glucose improvements after bariatric surgery. Our aim was to explore the role of GLP-1 in surgically-induced type 2 diabetes (T2D) improvement and its capacity to regulate human adipocyte inflammation. Methods: Basal circulating concentrations of GLP-1 as well as during an oral glucose tolerance test (OGTT) were measured in lean and obese volunteers with and without T2D (n = 93). In addition, GLP-1 levels were determined before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB) (n = 77). The impact of GLP-1 on inflammation signalling pathways was also evaluated. Results: We show that the reduced (p < 0.05) circulating levels of GLP-1 in obese T2D patients increased (p < 0.05) after RYGB. The area under the curve was significantly lower in obese patients with (p < 0.01) and without (p < 0.05) T2D compared to lean volunteers while obese patients with T2D exhibited decreased GLP-1 levels at baseline (p < 0.05) and 120 min (p < 0.01) after the OGTT. Importantly, higher (p < 0.05) pre-operative GLP-1 concentrations were found in patients with T2D remission after RYGB. We also revealed that exendin-4, a GLP-1 agonist, downregulated the expression of inflammation-related genes (IL1B, IL6, IL8, TNF) and, conversely, upregulated the mRNA levels of ADIPOQ in human visceral adipocytes. Furthermore, exendin-4 blocked (p < 0.05) LPS-induced inflammation in human adipocytes via downregulating the expression and secretion of key inflammatory markers. Conclusions: Our data indicate that GLP-1 may contribute to glycemic control and exert a role in T2D remission after RYGB. GLP-1 is also involved in limiting inflammation in human visceral adipocytes. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that adipose tissue inflammation is an important mechanism whereby obesity promotes cancer risk and progression. Since IL-32 is an important inflammatory and remodeling factor in obesity and is also related to colon cancer (CC) development, the aim of this study was to explore whether IL-32 could function as an inflammatory factor in human obesity-associated CC promoting a microenvironment favorable for tumor growth. Samples obtained from 84 subjects [27 lean (LN) and 57 obese (OB)] were used in the study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (49 without CC and 35 with CC). We show, for the first time, that obesity (p= 0.009) and CC (p= 0.026) increase circulating concentrations of IL-32α. Consistently, we further showed that gene (p< 0.05) and protein (p< 0.01) expression levels of IL-32α were upregulated in VAT from obese patients with CC. Additionally, we revealed thatIL32expression levels are enhanced by hypoxia and inflammation-related factors in HT-29 CC cells as well as that IL-32α is involved in the upregulation of inflammation (IL8, TNF, andCCL2) and extracellular matrix (ECM) remodeling (SPP1andMMP9) genes in HT-29 cancer cells. Additionally, we also demonstrate that the adipocyte-conditioned medium obtained from obese patients stimulates (p< 0.05) the expression ofIL32in human CC cells. These findings provide evidence of the potential involvement of IL-32 in the development of obesity-associated CC as a pro-inflammatory and ECM remodeling cytokine. [ABSTRACT FROM PUBLISHER]

Abstract: Adipose tissue is highly vascularized implying that angiogenesis takes place in its expansion. The aim of this study was to compare the concentrations of members of the vascular endothelial growth factor (VEGF) family in obesity. Serum concentrations of VEGFs were analyzed in 15 lean (BMI 20.3±2.5 kg/m2) and 24 obese (BMI 47.6±5.9 kg/m2) volunteers. Obese patients showed significantly increased circulating VEGF-A (150±104 vs. 296±160 pg/ml; P<.05), VEGF-B (2788±1038 vs. 4609±2202 arbitrary units; P<.05) and VEGF-C (13 453±5750 vs. 17 635±5117 pg/ml; P<.05) concentrations. Interestingly, levels of VEGF-D were reduced in obese individuals (538±301 vs. 270±122 pg/ml; P<.01). In addition, VEGF-A significantly decreased after weight loss following Roux-en-Y gastric bypass (BMI from 46.0±8.0 to 28.9±4.2 kg/m2 P<.0001 vs. initial) from 345±229 to 290±216 pg/ml (P<.01). Moreover, in order to corroborate the human findings VEGF-A levels were analyzed during the expansion of adipose tissue in two dynamic models of murine obesity. Serum VEGF-A was significantly increased after 12 weeks on a high-fat diet (43.3±9.0 vs. 29.7±9.1 pg/ml; P<.01) or in ob/ob mice (52.2±18.0 vs. 29.2±7.7 pg/ml; P<.01) and was normalized after leptin replacement in the latter (32.4±14.0 pg/ml; P<.01 vs. untreated ob/ob). Our data indicates the involvement of these factors in the expansion of adipose tissue that takes place in obesity in relation to the need for increased vascularization, suggesting that manipulation of the VEGF system may represent a potential target for the pharmacological treatment of obesity. [Copyright &y& Elsevier]