transforming-growth-factor-beta and Obesity--Morbid

Alcoholic liver disease remains a frequent and serious problem for increasing numbers of patients. Research has expanded our molecular understanding of the cellular basis of disease progression; however, translation into therapy is still hampered by a lack of suitable animal models for alcoholic liver disease, as well as from consequences of related liver damage due to malnutrition, hepatitis C virus infection, or abuse of other substances. Many patients with liver disease do not simply consume too much alcohol; they also suffer from comorbidities such as obesity or viral hepatitis, and/or may be addicted to other drugs besides alcohol. This review will summarize the currently available animal models to study liver disease due to either single causes or combinations of liver toxic substances/infections and alcohol.

Topics: Animals; Cytochrome P-450 CYP2E1; Disease Models, Animal; Hepatitis C, Chronic; Humans; Liver; Liver Diseases, Alcoholic; Malnutrition; Obesity, Morbid; Transforming Growth Factor beta

Surgical weight loss procedures like vertical sleeve gastrectomy (SG) are sufficient in resolving obesity comorbidities and are touted to reduce the burden of pro-inflammatory cytokines and augment the release of anti-inflammatory cytokines. Recent reports suggest a reduced improvement in weight resolution after SG in Black Americans (BA) versus White Americans (WA). The goal of this study was to determine if differences in immunoglobulin levels and general markers of inflammation after SG in Black Americans (BA) and White Americans (WA) may contribute to this differential resolution.. Personal information, anthropometric data, and plasma samples were collected from 58 participants (24 BA and 34 WA) before and 6 weeks after SG for the measurement of immunoglobulin A (IgA), IgG, IgM, C-reactive protein (CRP), and transforming growth factor (TGFβ). Logistic regression analysis was used to determine the relationship of measures of body size and weight and inflammatory markers.. Both IgG and CRP were significantly elevated in BA in comparison to WA prior to weight loss. Collectively, IgG, TGFβ, and CRP were all significantly reduced at six weeks following SG. CRP levels in BA were reduced to a similar extent as WA, but IgG levels were more dramatically reduced in BA than WA despite the overall higher starting concentration. No change was observed in IgA and IgM.. These data suggest that SG improves markers of immune function in both BA and WA. More diverse markers of immune health should be studied in future work.

Topics: Biomarkers; Black or African American; Cytokines; Gastrectomy; Humans; Immunoglobulin G; Immunoglobulin M; Obesity, Morbid; Transforming Growth Factor beta; Weight Loss; White

Extracellular vesicles (EVs) have been recently postulated as key players in metabolic disorders emerging as an alternative way of paracrine/endocrine communication. However, the nature of EVs shed by adipose tissue (AT) and their role in obesity is still very limited. Here, we isolated human morbid obese visceral (VAT) and subcutaneous (SAT) whole AT shed EVs from donors submitted to bariatric surgery to characterize their protein cargo by qualitative and quantitative/SWATH mass spectrometry analysis. We identified 574 different proteins shed by morbid obese VAT and 401 proteins in those from SAT, establishing the first obese AT EV proteome reference map. Only 50% of identified proteins in VAT vesicles were common to those in SAT; additionally, EVs shed by obese VAT showed more AT and obesity-related adipokines than SAT. Functional classification shows that obese VAT vesicles exhibit an enrichment of proteins implicated in AT inflammation and insulin resistance such as TGFBI, CAVN1, CD14, mimecan, thrombospondin-1, FABP-4 or AHNAK. Selected candidate biomarkers from the quantitative-SWATH analysis were validated in EVs from independent morbid obese and from moderate obese to lean individuals showing that morbid obese VAT vesicles are characterized by a diminution of syntenin 1 and the elevation of TGFBI and mimecan. Interestingly, TGFBI and mimecan containing vesicles could be detected and quantified at circulating level in plasma. Thus, a significant elevation of -TGFBI-EVs was detected on those obese patients with a history of T2D compared to nondiabetic, and an augmentation of mimecan-EVs in obese plasma compared to those in healthy lean individuals. Thus, we conclude that obese AT release functional EVs carrying AT and obesity candidate biomarkers which vary regarding the AT of origin. Our findings suggest that circulating EV-TGFBI may facilitate monitoring T2D status in obese patients, and EV-mimecan may be useful to track adiposity, and more precisely, visceral obesity.

Topics: Adipose Tissue, White; Adult; Biomarkers; Diabetes Mellitus, Type 2; Extracellular Matrix Proteins; Extracellular Vesicles; Female; Humans; Intercellular Signaling Peptides and Proteins; Intra-Abdominal Fat; Male; Middle Aged; Obesity; Obesity, Morbid; Proteins; Subcutaneous Fat; Syntenins; Transforming Growth Factor beta

Topics: Adult; CCN Intercellular Signaling Proteins; CD11 Antigens; Cell Line; Chemokine CCL2; Collagen; Female; Humans; Liver; Liver Cirrhosis; Male; Matrix Metalloproteinase 9; Middle Aged; Obesity, Morbid; Proto-Oncogene Proteins; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity and constitutes part of the metabolic syndrome, which have been associated with low serum vitamin D (VD). Due to known crosstalk between VD and transforming growth factor (TGF)-β signalling, VD has been proposed as an antifibrotic treatment.. We evaluated the association between VD, the vitamin D receptor (VDR) and liver fibrosis in primary human hepatic stellate cells (phHSC) and 106 morbidly obese patients with NAFLD.. Treating phHSC with VD ameliorated TGF-β-induced fibrogenesis via both VDR-dependent and VDR-independent mechanisms. Reduction of fibrogenic response was abolished in cells homozygous for GG at the A1012G single nucleotide polymorphisms within the VDR gene. Compared with healthy livers, NAFLD livers expressed higher levels of VDR mRNA and VDR fragments. VDR mRNA was lower in patients homozygous for GG at A1012G and expression of pro-fibrogenic genes was higher in patients carrying the G allele.. VD may be an antifibrotic treatment option early in the onset of fibrosis in specific genotypes for VDR. Known polymorphisms of the VDR may influence the response to VD treatment.

Topics: Adult; Cells, Cultured; Drug Evaluation, Preclinical; Female; Gene Expression Regulation; Gene Knockdown Techniques; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Polymorphism, Single Nucleotide; Receptors, Calcitriol; RNA, Messenger; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Vitamin D; Young Adult

Mucosal cytokines may be involved in the process of gastric bacterial contamination that may occur after Roux-en-Y bypass for morbid obesity in both gastric chambers, with inflammation and gastritis mostly in the excluded stomach.. A prospective observational study in a homogeneous population with nonspecific complaints.. Outpatient clinic of a large, public, academic hospital.. Subjects (n = 37; 26 [70.3%] female; mean +/- SD age, 42.4 +/- 9.9 years) seen a mean +/- SD of 7.3 +/- 1.4 years after Roux-en-Y gastric bypass and nonoperated on morbidly obese control subjects (n = 10; 7 [70%] female; mean +/- SD age, 44.0 +/- 8.9 years).. Enteroscopy was performed to collect samples for cytokine assays and bacteriologic studies.. Concentrations of tumor necrosis factor alpha and transforming growth factor beta in the gastric mucosa of both chambers in patients undergoing Roux-en-Y gastric bypass and correlation with bacterial overgrowth and Helicobacter pylori infection.. High microbial counts (>10(5) colony-forming units per milliliter) were detected in 22 (59.5%) and 7 (18.9%) of the 37 samples from the functional pouch and excluded reservoir, respectively; and H pylori investigation was positive in 6 of 37 samples (16.2%). The tumor necrosis factor alpha concentration (mean +/- SD, 2.1 +/- 1.9 pg/g of protein) and the transforming growth factor beta concentration (mean +/- SD, 24.2 +/- 12.8 pg/g of protein) in the excluded stomach, but not in the proximal pouch, were elevated with regard to the corpus or antrum of controls, and correlation with bacterial overgrowth and with H pylori infection was demonstrated.. Overexpression of tumor necrosis factor alpha and transforming growth factor beta occurred in the distal stomach, positive cytokine correlation with microbial invasion by H pylori and nonspecific germs was seen, and further studies addressing phenotypic and genotypic changes of gastric mucosa are recommended.

Topics: Adult; Aged; Case-Control Studies; Female; Follow-Up Studies; Gastric Bypass; Gastric Mucosa; Gastric Stump; Helicobacter pylori; Humans; Male; Middle Aged; Obesity, Morbid; Prospective Studies; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Obesity is associated with insulin resistance in skeletal muscle; accordingly, weight loss dramatically improves insulin action. We sought to identify molecular remodeling of muscle commensurate with weight loss that could explain improvements in insulin action. Muscle from morbidly obese women was studied before and after gastric bypass surgery. Gastric bypass surgery significantly reduced body mass by approximately 45% and improved insulin action. We then assessed mRNA profiles using a stringent statistical analysis (statistical concordance with three probe set algorithms), with validation in a cross-sectional study of lean (n = 8) vs. morbidly obese (n = 8) muscle. Growth factor receptor-bound protein 14 (GRB14), glycerol-3-phosphate dehydrogenase 1 (GPD1), and growth differentiation factor 8 (GDF8; myostatin) significantly decreased approximately 2.4-, 2.2-, and 2.4-fold, respectively, after weight loss (gastric bypass). Increased expression of these transcripts was associated with increased obesity in the cross-sectional group (lean vs. morbidly obese muscle). Each transcript was validated by real-time quantitative RT-PCR assays in both study groups. Using Ingenuity Pathway Analysis, we show that all three transcripts are involved in the same regulatory network including AKT1, IGF1, TNF, PPARG, and INS. These results suggest that GRB14, GPD1, and GDF8 are weight loss-responsive genes in skeletal muscle and that the observed transcriptional modulation of these would be expected to improve insulin signaling, decrease triglyceride synthesis, and increase muscle mass, respectively, with weight loss. Thus our data provide a possible regulatory pathway involved in the development of insulin resistance in the morbidly obese state, and improvement of insulin resistance with weight loss.

Topics: Adaptor Proteins, Signal Transducing; Adult; Biopsy, Needle; Body Mass Index; Cross-Sectional Studies; Cytokines; Female; Gastric Bypass; Gene Expression Profiling; Glycerol-3-Phosphate Dehydrogenase (NAD+); Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Longitudinal Studies; Middle Aged; Models, Biological; Myostatin; Obesity, Morbid; Postoperative Period; Quadriceps Muscle; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor beta; Weight Loss

The present studies examined the effect of obesity in humans on the release of transforming growth factor beta1 (TGF-beta1) by human adipose tissue. The regulation of TGF-beta1 release by adipose tissue as well as the question of whether its release is due to the adipocytes or the nonfat cells in adipose tissue was also examined. There was a statistically significant (r=0.50) correlation between the body mass index of the fat donors and the subsequent release of TGF-beta1 release by subcutaneous adipose tissue. There was also a positive correlation between total TGF-beta1 release by adipose tissue explants and body fat content (r=0.69). The question of whether tumor necrosis factor alpha (TNF-alpha) and/or interleukin 1 beta (IL-1 beta) regulate the release of TGF-beta1 was investigated by incubation of adipose tissue explants with a soluble human TNF-alpha receptor (etanercept) and a neutralizing antihuman IL-1 beta antibody. The release of TGF-beta1 over 48 hours by adipose tissue explants was significantly enhanced in the presence of both the inhibitor of TNF-alpha and of IL-1 beta. It is of interest, in view of the elevated circulating insulin in blood of morbidly obese women, that the release of TGF-beta1 by adipose tissue was enhanced in the presence of insulin. The question of whether the release of TGF-beta1 by human adipose tissue explants was primarily due to adipocytes, as is the case for leptin, or the nonfat cells present in human adipose tissue, as is the case for IL-8 and prostaglandin E(2), was examined. The release of TGF-beta1 was primarily by the nonfat cells of human adipose tissue because release by adipocytes was less than 10% of that by the nonfat cells of adipose tissue.

Topics: Adipocytes; Adult; Body Mass Index; Cells, Cultured; Female; Humans; Intra-Abdominal Fat; Obesity, Morbid; Subcutaneous Fat; Transforming Growth Factor beta; Transforming Growth Factor beta1

To investigate the tissue factor (TF) pathway in clinical obesity and associated metabolic syndrome.. Thirty-seven morbidly obese patients (4 men; BMI, 48 +/- 7 kg/m(2); range, 42 to 53 kg/m(2)), undergoing elective gastroplasty for the induction of weight loss, were examined for hemostatic, metabolic, and inflammatory parameters at baseline and 14 +/- 5 months postoperatively.. Weight loss significantly reduced circulating plasma TF (314 +/- 181 vs. 235 +/- 113 pg/mL, p = 0.04), coagulation factor VII (130 +/- 22% vs. 113 +/- 19%, p = 0.023), and prothrombin fragment F1.2 (2.4 +/- 3.4 vs. 1.14 +/- 1.1 nM, p = 0.04) and normalized glucose metabolism in 50% of obese patients preoperatively classified as diabetic or of impaired glucose tolerance. The postoperative decrease in plasma TF correlated with the decrease of F1.2 (r = 0.56; p = 0.005), a marker of in vivo thrombin formation. In subgroup analysis stratified by preoperative glucose tolerance, baseline circulating TF (402.6 +/- 141.6 vs. 176.2 +/- 58.2, p < 0.001) and TF decrease after gastroplasty (DeltaTF: 164.7 +/- 51.4 vs. -81 +/- 31 pg/mL, p = 0.02) were significantly higher in obese patients with impaired glucose tolerance than in patients with normal glucose tolerance.. Procoagulant TF is significantly reduced with weight loss and may contribute to a reduction in cardiovascular risk associated with obesity.

Topics: Adult; Blood Glucose; Body Mass Index; C-Reactive Protein; Factor VII; Female; Gastroplasty; Glycated Hemoglobin; Humans; Insulin; Interleukin-6; Leptin; Lipoproteins; Longitudinal Studies; Male; Obesity, Morbid; Prospective Studies; Prothrombin Time; Statistics, Nonparametric; Thromboplastin; Transforming Growth Factor beta; Weight Loss

Insulin resistance and systemic hypertension are predictors of advanced fibrosis in obese patients with non-alcoholic fatty liver disease (NAFLD). Genetic factors may also be important. We hypothesize that high angiotensinogen (AT) and transforming growth factor-beta1 (TGF-beta1) producing genotypes increase the risk of liver fibrosis in obese subjects with NAFLD.. One hundred and five of 130 consecutive severely obese patients having a liver biopsy at the time of laparoscopic obesity surgery agreed to have genotype analysis. Influence of specific genotype or combination of genotypes on the stage of hepatic fibrosis was assessed after controlling for known risk factors.. There was no fibrosis in 70 (67%), stages 1-2 in 21 (20%) and stages 3-4 fibrosis in 14 (13%) of subjects. There was no relationship between either high AT or TGF-beta1 producing genotypes alone and hepatic fibrosis after controlling for confounding factors. However, advanced hepatic fibrosis occurred in five of 13 subjects (odds ratio 5.7, 95% confidence interval 1.5-21.2, P=0.005) who inherited both high AT and TGF-beta1 producing polymorphisms.. The combination of high AT and TGF-beta1 producing polymorphisms is associated with advanced hepatic fibrosis in obese patients with NAFLD. These findings support the hypothesis that angiotensin II stimulated TGF-beta1 production may promote hepatic fibrosis.

Topics: Adult; Fatty Liver; Female; Gene Frequency; Genotype; Humans; Liver Cirrhosis; Male; Middle Aged; Obesity, Morbid; Polymorphism, Genetic; Predictive Value of Tests; Risk Factors; Severity of Illness Index; Transforming Growth Factor beta; Transforming Growth Factor beta1

In adipose tissue from both obese mice and humans, plasminogen activator inhibitor 1 (PAI-1) expression has been reported to be upregulated to levels of increased plasma PAI-1. This elevated expression has been shown to be partly controlled by tumor necrosis factor (TNF)-alpha in mice. In humans, increased PAI-1 expression is associated with insulin resistance characterized by visceral fat accumulation. Therefore, the aim of this study was to investigate the expression pattern of PAI-1 and TNF-alpha (antigen and mRNA) in visceral human adipose fat in comparison with subcutaneous (SC) fat. Because transforming growth factor (TGF)-beta1 is a potent inducer of PAI-1 synthesis and has been shown to influence adipocyte metabolism, this work was extended to TGF-beta1 quantification. A total of 32 obese individuals (BMI 42 +/- 6.8 kg/m2) were investigated. Freshly collected visceral adipose tissue did not exhibit a higher content of PAI-1 or TGF-beta1 than did SC tissue. Although most of the TNF-alpha values were at the detection limit of the methods, TNF-alpha antigen was 3-fold higher and TNF-alpha mRNA was 1.2-fold higher in visceral fat. The levels of tissue TGF-beta1 antigen correlated well with those of PAI-1 antigen, regardless of the fat depot studied (SC tissue: n = 21, r = 0.72, P = 0.0006; visceral tissue: n = 20, r = 0.49, P < 0.03), and they were both significantly associated with BMI. Conversely, no relationship was observed between the levels of TNF-alpha and PAI-1 or TNF-alpha and BMI. Tissue PAI-1 levels were also significantly correlated with those of circulating PAI-1. These results describe, in severe obesity, a proportional increase in tissue PAI-1 and TGF-beta1 in visceral and SC tissues. This increased PAI-1 expression could be the result of tissue cytokine disturbances, such as elevated TGF-beta1 expression.

Topics: Adipose Tissue; Adult; Animals; Body Mass Index; Female; Humans; Male; Mice; Obesity, Morbid; Plasminogen Activator Inhibitor 1; Regression Analysis; RNA, Messenger; Skin; Transcription, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Viscera