Thromboxane Production in Morbidly Obese Subjects

Graziani, Francesca; Biasucci, Luigi M.; Cialdella, Pio; Liuzzo, Giovanna; Giubilato, Simona; Bona, Roberta Della; Pulcinelli, Fabio M.; Iaconelli, Amerigo; Mingrone, Geltrude; Crea, Filippo

doi:10.1016/j.amjcard.2011.01.053

Cited by 44 publications

(35 citation statements)

References 24 publications

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“…The expression of Tbxas and Tbxa2r in white adipose tissue was markedly increased in genetic and dietary mouse models of obesity. Our mouse expression data on Tbxa2 are consistent with recent human studies showing that serum thromboxane B2 levels are elevated in obese and/or diabetic subjects (18,41) and that weight reduction from decreased caloric intake or pioglitazone treatment leads to reduced urinary thromboxane B2 levels (4, 9). Furthermore, our genetic loss-of-function studies in Tbxas KO mice provide functional evidence to support a role for thromboxane in modulating peripheral tissue insulin sensitivity and glucose homeostasis.…”

Section: Discussionsupporting

confidence: 78%

“…Excess thromboxane A2 has also been linked to atherosclerosis (27,31), glomerulonephritis (42), and hypertension (8,13). In humans, serum levels of thromboxane B2 (a stable metabolite of thromboxane A2) are found to be significantly elevated in obese subjects relative to lean individuals (18); paradoxically, in morbidly obese (average BMI of 49) but insulin-sensitive subjects, serum thromboxane B2 levels are found to be lower than in healthy lean individuals (18). In the context of diabetes, both type 1 and type 2 diabetic individuals have higher serum thromboxane B2 levels (41); the production of thromboxane B2 is also correlated with fasting plasma glucose and hemoglobin A 1c (Hb A 1c ).…”

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confidence: 99%

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Thromboxane synthase deficiency improves insulin action and attenuates adipose tissue fibrosis

Lei

Rodriguez

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Thromboxane A2, an arachidonic acid-derived eicosanoid generated by thromboxane synthase (TBXAS), plays critical roles in hemostasis and inflammation. However, the contribution of thromboxane A2 to obesity-linked metabolic dysfunction remains incompletely understood. Here, we used in vitro and mouse models to better define the role of TBXAS in metabolic homeostasis. We found that adipose expression of Tbxas and thromboxane A2 receptor ( Tbxa2r) was significantly upregulated in genetic and dietary mouse models of obesity and diabetes. Expression of Tbxas and Tbxa2r was detected in adipose stromal cells, including macrophages. Furthermore, stimulation of macrophages with interferon-γ or resistin factors known to be upregulated in obesity induced Tbxas and Tbxa2r expression. Mice lacking Tbxas had similar weight gain, food intake, and energy expenditure. However, loss of Tbxas markedly enhanced insulin sensitivity in mice fed a low-fat diet. Improvement in glucose homeostasis was correlated with the upregulated expression of multiple secreted metabolic regulators ( Ctrp3, Ctrp9, and Ctrp12) in the visceral fat depot. Following a challenge with a high-fat diet, Tbxas deficiency led to attenuated adipose tissue fibrosis and reduced circulating IL-6 levels without adipose tissue macrophages being affected; however, these changes were not sufficient to improve whole body insulin action. Together, our results highlight a novel, diet-dependent role for thromboxane A2 in modulating peripheral tissue insulin sensitivity and adipose tissue fibrosis.

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Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

Thromboxane synthase deficiency improves insulin action and attenuates adipose tissue fibrosis

Lei

Rodriguez

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Much as the relationship of HAPR with glycemic and lipid control of DM2 has been well documented, only few small studies regarding the association of platelet reactivity with insulin resistance and adipokine concentrations have been conducted so far [5,26–28]. Among 60 healthy women, a lower insulin sensitivity index was predictive of higher urine 11-dehydro-TXB 2 concentration and improvement in insulin sensitivity resulted in decreasing urinary 11-dehydro-TXB 2 excretion [26].…”

Section: Introductionmentioning

confidence: 99%

Younger age, higher body mass index and lower adiponectin concentration predict higher serum thromboxane B2 level in aspirin-treated patients with type 2 diabetes: an observational study

Kapłon‐Cieślicka

Postuła

Rosiak

et al. 2014

Cardiovasc Diabetol

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BackgroundEvidence from the literature suggests diminished acetylsalicylic acid (ASA) treatment efficacy in type 2 diabetes (DM2). High on-aspirin platelet reactivity (HAPR) in DM2 has been linked to poor glycemic and lipid control. However, there are no consistent data on the association between HAPR and insulin resistance or adipose tissue metabolic activity. The aim of this study was to assess the relationship between laboratory response to ASA and metabolic control, insulin resistance and adipokines in DM2.MethodsA total of 186 DM2 patients treated with oral antidiabetic drugs and receiving 75 mg ASA daily were included in the analysis. Response to ASA was assessed by measuring serum thromboxane B2 (TXB2) concentration and expressed as quartiles of TXB2 level. The achievement of treatment targets in terms of glycemic and lipid control, insulin resistance parameters (including Homeostatic Model Assessment-Insulin Resistance, HOMA-IR, index), and serum concentrations of high-molecular weight (HMW) adiponectin, leptin and resistin, were evaluated in all patients. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors of serum TXB2 concentration above the upper quartile and above the median.ResultsSignificant trends in age, body mass index (BMI), HOMA-IR, HMW adiponectin concentration, C-reactive protein concentration and the frequency of achieving target triglyceride levels were observed across increasing quartiles of TXB2. In a multivariate analysis, only younger age and higher BMI were independent predictors of TXB2 concentration above the upper quartile, while younger age and lower HMW adiponectin concentration were predictors of TXB2 concentration above the median.ConclusionsThese results suggest that in DM2, the most important predictor of HAPR is younger age. Younger DM2 patients may therefore require total daily ASA doses higher than 75 mg, preferably as a twice-daily regimen, to achieve full therapeutic effect. Higher BMI and lower HMW adiponectin concentration were also associated with less potent ASA effect. This is the first study to demonstrate an association of lower adiponectin concentration with higher serum TXB2 level in patients treated with ASA.

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“…Aberrant TXA 2 production is associated with obesity; in the nonpregnant state, serum TXB 2 (a stable metabolite of TXA 2 ) levels are higher in obese, and lower in morbidly obese, women than their normal weight counterparts [41]. Abnormal artery function in obese pregnancies may thus arise from aberrant levels of and/or altered responses to TXA 2 .…”

Section: Discussionmentioning

confidence: 98%

Maternal Obesity Impairs Specific Regulatory Pathways in Human Myometrial Arteries1

Hayward

Cowley

Mills

et al. 2014

Biology of Reproduction

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Obese women (body mass index ≥30 kg/m(2)) are at greater risk than normal weight women of pregnancy complications associated with maternal and infant morbidity, particularly the development of cardiovascular disease and metabolic disorders in later life; why this occurs is unknown. Nonpregnant, obese individuals exhibit systemic vascular endothelial dysfunction. We tested the hypothesis that obese pregnant women have altered myometrial arterial function compared to pregnant women of normal (18-24 kg/m(2)) and overweight (25-29 kg/m(2)) body mass index. Responses to vasoconstrictors, U46619 (thromboxane mimetic) and arginine vasopressin, and vasodilators, bradykinin and the nitric oxide donor sodium nitroprusside, were assessed by wire myography in myometrial arteries from normal weight (n = 18), overweight (n = 18), and obese (n = 20) women with uncomplicated pregnancies. Thromboxane-prostanoid receptor expression was assessed using immunostaining in myometrial arteries of normal weight and obese women. Vasoconstriction and vasodilatation were impaired in myometrial arteries from obese women with otherwise uncomplicated pregnancies. Disparate agonist responses suggest that vascular function in obese women is not globally dysregulated but may be specific to thromboxane and nitric oxide pathways. Because obesity rates are escalating, it is important to identify the mechanisms underlying impaired vascular function and establish why some obese women compensate for vascular dysfunction and some do not. Future studies are needed to determine whether central adiposity results in an altered endocrine milieu that may promote vascular dysfunction by altering the function of perivascular adipose tissue.

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Thromboxane Production in Morbidly Obese Subjects

Cited by 44 publications

References 24 publications

Thromboxane synthase deficiency improves insulin action and attenuates adipose tissue fibrosis

Thromboxane synthase deficiency improves insulin action and attenuates adipose tissue fibrosis

Younger age, higher body mass index and lower adiponectin concentration predict higher serum thromboxane B2 level in aspirin-treated patients with type 2 diabetes: an observational study

Maternal Obesity Impairs Specific Regulatory Pathways in Human Myometrial Arteries1

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