endothelin-1 and Obesity--Morbid

Endothelial dysfunction and inflammation are present in both type 2 diabetes mellitus (T2DM) and obesity. In this paper we compared the role of weight loss and of glycaemic control in determining circulating levels of ICAM-1, endothelin-1 (ET-1), and E-selectin in patients with morbid (grade 3) obesity.. ICAM-1, E-selectin, and ET-1 were higher in obese patients (n=96) than in lean controls (n=30); among obese patients, the three molecules were higher in T2DM patients (n=26) than in patients with normal (NGT, n=43) or impaired (IGT, n=27) glucose tolerance. Sixty-eight obese patients had a significant weight loss induced by bariatric surgery, and showed a significant decrease in blood glucose, HbA1c and all molecules, so that ICAM-1, E-selectin, and ET-1 were not different in NGT, IGT and T2DM patients, and in lean controls; in 13 patients with a small weight loss induced by diet, changes were not significant, in spite of a significant reduction in blood glucose and HbA1c. At stepwise regression, changes in ICAM-1, ET-1, and E-selectin significantly correlated only with change in body mass index.. These data indicate that weight loss is more important than glycaemic control in regulating circulating levels of ICAM-1, ET-1, E-selectin in morbidly obese subjects.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; E-Selectin; Endothelin-1; Female; Follow-Up Studies; Glucose Intolerance; Glycated Hemoglobin; Humans; Insulin Resistance; Intercellular Adhesion Molecule-1; Male; Matched-Pair Analysis; Middle Aged; Obesity, Morbid; Reference Values; Regression Analysis; Weight Loss

Hypertension is one of the most prevalent diseases worldwide. Increased synthesis of the vasoconstrictor peptide endothelin 1 (encoded by EDN1) might be responsible for high blood pressure. The present study further confirmed the abnormal EDN1 upregulation within adipose tissue-derived stromal cells (ADSCs) derived from morbidly obese subjects. The overexpression of EDN1 in ADSCs derived from non-obese subjects significantly promoted the proliferation and migration of HUVECs and tube formation by human umbilical vein endothelial cell (HUVEC). Transcription factor NR4A3 was positively correlated with EDN1, binding to EDN1 promoter region to upregulate EDN1 expression. Similarly, the overexpression of NR4A3 in ADSCs derived from non-obese subjects significantly promoted the proliferation and migration of HUVECs and tube formation by HUVECs, as well as EDN1 protein levels in ADSCs. However, the effects of NR4A3 overexpression on EDN1 protein levels in ADSCs and the proliferation and migration of HUVECs and tube formation by HUVECs were significantly reversed by EDN1 silencing in ADSCs. In conclusion, NR4A3 is abnormally upregulated in ADSCs derived from morbidly obese subjects; NR4A3 could promote HUVEC angiogenesis through binding to EDN1 promoter and upregulating EDN1 expression.

Topics: Adipose Tissue; Cell Survival; DNA-Binding Proteins; Endothelin-1; Human Umbilical Vein Endothelial Cells; Humans; Neovascularization, Physiologic; Obesity, Morbid; Promoter Regions, Genetic; Protein Binding; Receptors, Steroid; Receptors, Thyroid Hormone; Stromal Cells; Up-Regulation

Obesity and insulin resistance are positively correlated with plasma endothelin-1 (ET-1) levels; however, the mechanisms leading to increased ET-1 are not understood. Similarly, the full physiological complexity of ET-1 has yet to be described, especially in obesity. To date, one of the best treatments available for morbid obesity is bariatric surgery to quickly reduce body fat and the factors associated with obesity-related disease; however, the effects of vertical sleeve gastrectomy (SG) on plasma ET-1 have not been described.. To determine if SG will reduce plasma ET-1 levels and to determine if plasma ET-1 concentration is associated with weight loss after surgery.. The studies were undertaken at a University Hospital.. This was tested by measuring plasma ET-1 levels from 12 obese patients before and after SG. All data were collected from clinic visits before SG, 6 weeks after SG, and 6 months after surgery.. At 6 weeks after SG, plasma ET-1 levels increased by 24%; however, after 6 months, there was a 27% decrease compared with presurgery. Average weight loss in this cohort was 11.3% ± 2.4% body weight after 6 weeks and 21.4% ± 5.7% body weight after 6 months. Interestingly, we observed an inverse relationship between baseline plasma ET-1 and percent body weight loss (R. Our results indicate that SG reduces plasma ET-1 levels, a possible mechanism for improved metabolic risk in these patients. These data also suggest that ET-1 may serve as a predictor of weight loss after bariatric surgery.

Topics: Adult; Bariatric Surgery; Body Mass Index; Cohort Studies; Endothelin-1; Female; Gastrectomy; Humans; Male; Middle Aged; Obesity, Morbid; Time Factors; Treatment Outcome; Weight Loss

The aim of this study was to determine if weight loss following Roux-en-Y gastric bypass (RYGB) surgery in morbidly obese patients is associated with a decrease in plasma concentrations of neprilysin, mediators of the renin angiotensin system (RAS), catecholamines and endothelin-1, and also with an increase in the concentrations of vasodilators. Fasting blood samples were obtained from 15 patients with morbid obesity and diabetes prior to and 6 months after RYGB surgery. Circulating levels of neprilysin, vasoconstrictors, vasodilators, and the mRNA expression of related genes in circulating mononuclear cells (MNC) were measured. Six months after RYGB surgery the concentrations of neprilysin, angiotensinogen, angiotensin II, renin and endothelin-1 fell significantly by 27 ±16%, 22 ±10%, 22 ±8%, 35 ±13% and 17 ±6% (P < .05 for all), respectively, while ANP concentrations increased significantly by 24 ±13%. There was no significant change in aldosterone, BNP, cAMP or cGMP concentrations, or angiotensin converting enzyme (ACE) expression. These changes may contribute to the reduction of congestive cardiac failure and blood pressure risks after RYGB surgery.

Topics: Bariatric Surgery; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Endothelin-1; Female; Glycated Hemoglobin; Heart Failure; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Neprilysin; Obesity, Morbid; Postoperative Period; Prospective Studies; Renin-Angiotensin System; Risk; Weight Loss

We assessed the impact of vascular and perivascular tumour necrosis factor-alpha (TNF-α) on the endothelin (ET)-1/nitric oxide (NO) system and the molecular pathways involved in small arteries from visceral fat of obese patients (Obese) and Controls.. Isolated small arteries from 16 Obese and 14 Controls were evaluated on a pressurized micromyograph. Endogenous ET-1 activity was assessed by the ETA blocker BQ-123. TNF-α and NO were tested by anti-TNF-α infliximab (IFX) and N(ω)-nitro-l-arginine methylester (L-NAME). Gene and protein expression of TNF-α, ET-1, ETA, and ETB receptors were determined by RT-PCR and IHC on arterial wall and in isolated adipocytes. Obese showed a blunted L-NAME-induced vasoconstriction, which was potentiated by IFX, and an increased relaxation to BQ-123, unaffected by L-NAME but attenuated by IFX. Perivascular adipose tissue (PVAT) removal reversed these effects. Obese showed intravascular superoxide excess, which was decreased by apocynin (NAD(P)H oxidase inhibitor), L-NAME, and BQ-123 incubations, and abolished by IFX. An increased vascular expression of ET-1, ETA, and ETB receptors, and higher vascular/perivascular TNF-α and TNF-α receptor expression were also detected. The arterial expression and phosphorylation of c-Jun N-terminal kinase (JNK) were higher in Obese vs. Controls, and downregulated by IFX.. In small arteries of Obese, PVAT-derived TNF-α excess, and an increased vascular expression of ET-1 and ETA receptor, contribute to the ET-1/NO system imbalance, by impairing tonic NO release. Reactive oxygen species excess, via NAD(P)H oxidase activation, induces the endothelial nitric oxide synthase uncoupling, which in turn generates superoxide and impairs NO production. The up-regulated JNK pathway represents a crucial molecular signalling involved in this process.

Topics: Case-Control Studies; Cells, Cultured; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Female; Humans; Infliximab; Intra-Abdominal Fat; Male; Microvessels; Middle Aged; NG-Nitroarginine Methyl Ester; Nitric Oxide; Obesity, Morbid; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Tumor Necrosis Factor; Superoxides; Tumor Necrosis Factor-alpha; Vasoconstriction

Decrease of both visceral fat (surgery, physical exercise) and subcutaneous fat (liposuction) is accompanied by improvement of insulin sensitivity.. In this study, metabolic variables (glucose, insulin, high-density lipoprotein-cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, uric acid, ferritin) and adhesion molecules (ICAM-1, entothelin-1, E-selectin) were determined in 126 morbidly obese subjects before and 1 year after bariatric restrictive surgery (laparoscopic gastric banding) and correlated with anthropometric measures, i.e., body mass index (BMI) and waist circumference (waist), and with echographic measures of thickness of visceral (usVT) and subcutaneous (usST) abdominal fat.. Under basal conditions and after 1 year, metabolic variables correlated with BMI and waist (r from 0.157 to 0.507, p from 0.0182 to 0.0001) and with usVT (r from 0.211 to 0.512, p from 0.05 to 0.0001); insulin also correlated with usST, and adhesion molecules only correlated with BMI and usVT (r from 0.341 to 0.502, p from 0.0066 to 0.0001). Changes of metabolic variables correlated with changes of BMI and waist (r from 0.163 to 0.356, p from 0.0328 to 0.0001) and with usVT changes (r from 0.211 to 0.361, p from 0.0339 to 0.0002); changes of adhesion molecules only correlated with BMI and usVT changes (r from 0.227 to 0.361, p from 0.0444 to 0.0108). Changes of metabolic variables and of adhesion molecules virtually never correlated with changes of usST.. These data indicate that in morbid obesity, most metabolic abnormalities are associated with visceral fat and that their improvements after weight loss are associated with decrease of visceral fat.

Topics: Adolescent; Adult; Aged; Blood Glucose; Body Fat Distribution; Body Mass Index; Body Weight; E-Selectin; Endothelin-1; Female; Gastroplasty; Humans; Insulin; Intercellular Adhesion Molecule-1; Intra-Abdominal Fat; Male; Middle Aged; Obesity, Morbid; Regression Analysis; Subcutaneous Fat, Abdominal; Ultrasonography; Weight Loss; Young Adult

Hypertension and central obesity are two conditions closely linked, but the mechanisms responsible for obesity-associated hypertension are still unclear. In the last few years, several studies addressed the role of endothelin-1 (ET-1) in the development and maintenance of hypertension. This study was designed to evaluate plasma ET-1 in normotensive and hypertensive central obese subjects compared with a lean healthy group. Our final goal was to analyze the relationship between plasma ET-1, blood pressure, and left ventricular structure and function in central obese subjects (both normotensives and hypertensives). ET-levels have been assessed by the radioimmunoassay method in 20 lean normotensives and in 57 central obese subjects; 30 of them were hypertensives and 27 of them were normotensives. Twenty-four-hour mean blood pressure (MBP/24 h) by noninvasive ambulatory blood pressure monitoring, left ventricular mass/ height (LVM/H), and left ventricular ejection fraction (LVEF) by echocardiography and peak filling rate (PFR) by radionuclide study were also measured. ET levels were significantly (P < .05) higher in obese hypertensives and obese normotensives than in lean normotensives. In addition, ET levels were significantly (P < .05) higher in obese hypertensives than in obese normotensives. ET were directly related to LVM/ H (r = 0.86; P < .001) and MBP/24 h (r = 0.48; P < .009) but only in obese hypertensives. Multiple regression analysis indicated that ET-1 plasma levels remain an independent predictor of MBP/ 24 h and LVM/H also when age was included in the analysis. These data suggest that obesity-associated hypertension is characterized by an endothelial dysfunction that may contribute to the higher cardiovascular risk detectable in these patients.

Topics: Adult; Blood Pressure Monitoring, Ambulatory; Body Constitution; Body Height; Body Mass Index; Echocardiography; Endothelin-1; Female; Heart Rate; Humans; Hypertension; Male; Obesity, Morbid; Radioimmunoassay; Radionuclide Angiography; Regression Analysis; Stroke Volume; Ventricular Dysfunction, Left