Effect of Leptin on Arterial Thrombosis Following Vascular Injury in Mice

Bodary, Peter F.

doi:10.1001/jama.287.13.1706

Cited by 220 publications

(158 citation statements)

References 16 publications

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“…Consistent with a direct role of leptin in thrombosis, experimental studies have shown that ob/ob mice that are defective in leptin secretion, show impaired thrombus formation in response to vascular injury that is subsequently restored by leptin administration. [16][17][18] However, in the present study, the lack of robust correlation between leptin and platelet-MPs, a reliable marker of platelet activation, did not substantiate the view that leptin directly modulates platelet activation, even though leptin binding to its platelet receptor promotes aggregation. [16][17][18] Leukocyte-derived MPs could be key factors in pathways activated by obesity-mediated inflammation.…”

Section: Obesity Associated Inflammation and Vascular Damagecontrasting

confidence: 61%

Short-term very low-calorie diet in obese females improves the haemostatic balance through the reduction of leptin levels, PAI-1 concentrations and a diminished release of platelet and leukocyte-derived microparticles

et al. 2011

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Background: In obesity, metabolic stress and inflammation in injured tissues could favour enhanced shedding of procoagulant microparticles (MPs). At sites of endothelium injury, the swift recruitment of procoagulant leukocyte-derived MPs enables the initiation of blood coagulation and thrombus growth. Objectives: In obese females, we sought to evaluate the impact of a very low-calorie diet (VLCD) on procoagulant MP levels, fibrinolytic status, inflammation and endothelium damage. Methods: Circulating biomarkers of vascular damage, fibrinolytic status, platelet activation and inflammation were measured before, 30 and 90 days after starting a short-term VLCD. MPs were measured by flow cytometry and capture assays. Their procoagulant potential was quantified using functional prothrombinase assays and their cellular origin were determined using flow cytometry (endothelium, platelet, leukocyte, lymphocyte and erythrocyte-derived MP) or capture assays. Results: A total of 24 obese females (39 ± 10 years) with a mean body mass index of 35 ± 4 kg m À2 were prospectively enroled. Procoagulant leukocyte-derived MPs were associated with the waist circumference at baseline (r ¼ 0.534; P ¼ 0.010) and at 90 days follow-up (r ¼ 0.487; P ¼ 0.021). At 90 days, weight reduction (À9.8%) was associated with a lowering of blood pressure, improvement of metabolic parameters and a significant reduction of plasminogen activator inhibitor-1 (PAI-1) (À38%), procoagulant platelet-derived MPs (À43%), leukocyte-derived MPs (À28%) and leptin (À32%) levels. Conclusion: In obese females, a short-term VLCD results in an overall improvement of the haemostatic balance characterized by the reduction of PAI-levels, diminished release of platelet and leukocyte-derived MPs and a reduction in leptin levels, an adipocyte-derived cytokine.

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Section: Obesity Associated Inflammation and Vascular Damagecontrasting

confidence: 61%

Short-term very low-calorie diet in obese females improves the haemostatic balance through the reduction of leptin levels, PAI-1 concentrations and a diminished release of platelet and leukocyte-derived microparticles

et al. 2011

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“…7 Although leptin's major role seems to be in the regulation of body weight and energy metabolism, several evidences suggest that this hormone could be involved in other pathophysiological mechanisms, such as immune function, angiogenesis, bone formation and fertility, and the expression of leptin receptor has been demonstrated in a variety of tissues. [8][9][10][11][12][13] The long form of leptin receptor (ObRb) has been found on platelet membrane, 14 and it has been demonstrated that leptin-deficient ob/ob mice, 15,16 and wild-type mice treated with a leptin-neutralizing antibody, 17 develop unstable thrombi and an attenuated thrombotic response to arterial injury, and they exhibit a defective platelet aggregation. Leptin also promotes thrombosis in the mouse, and it potentiates the aggregation of murine platelets in vitro in a leptin receptor-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients

et al. 2006

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Objective: To verify whether platelet responsiveness to leptin is associated with metabolic syndrome risk factors. Design: Cross-sectional study. Subjects: We studied 169 consecutive patients, mean age ¼ 43.679.9 years, with overweight (N ¼ 57) or obesity (N ¼ 112). Measurements: Cluster analysis was used to generate three clusters based on platelet responsiveness to increasing doses of leptin. Profiles of metabolic syndrome risk factors of the three clusters were compared by discriminant analysis. Results: Platelet responsiveness to leptin was absent in cluster 1, whereas cluster 3 had the greatest platelet aggregation response to leptin pre-incubation. Plasma leptin levels significantly decreased from cluster 1 to cluster 3 in both gender. Patients in cluster 2 had an intermediate profile of leptin responsiveness. Highest body mass index (BMI) values were more frequent in non-responders, whereas the prevalence of high waist circumference, as well as hypertriglyceridemia and hypertension, increased with increasing responsiveness to leptin from cluster 1 to cluster 3. Pattern of metabolic syndrome risk factors qualified as group specific in 69.0% of the cluster 1, 54.9% of the cluster 2 and 55.8% of the cluster 3. Circulating leptin, waist circumference, plasma triglycerides and BMI defined distinctive patterns of metabolic syndrome risk factors in the clusters. Conclusions: In overweight and obese outpatients, metabolic syndrome risk factors parallel to some extent platelet responsiveness to leptin. Such a correlation involves plasma leptin levels, waist circumference, plasma triglycerides and BMI, and may contribute to the excess risk of cardiovascular events in overweight and obese patients.

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“…10 Recent studies demonstrate that leptin is able to accelerate arterial thrombosis; thus, suggesting a mechanism for atherothrombotic disease in obesity. 11,12 The long form of leptin receptor (ObRb) has been found on the platelet membrane, and it has been suggested that leptin may promote the aggregation of human platelets through the activation of its receptor and postreceptor phosphorylation of STAT proteins. 13 The ability of leptin to enhance platelet aggregation has been recently confirmed in ob/ob mice 11 and healthy subjects.…”

Section: Introductionmentioning

confidence: 99%

Identifying pathways involved in leptin-dependent aggregation of human platelets

et al. 2004

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OBJECTIVE:To investigate the role of phospholipase C (PLC), phospholipase A 2 (PLA 2 ), calcium, and protein kinase C (PKC) in mediating leptin-enhanced aggregation of human platelets. DESIGN: In vitro, ex vivo study. SETTING: Outpatient's Service for Prevention and Treatment of Obesity at the University Hospital of Messina, Italy. SUBJECTS: In total, 14 healthy normal-weight male (age 31.471.9 y; body mass index 22.770.6 kg/m 2 ) subjects. MEASUREMENTS: Adenosine diphosphate-(ADP-) induced platelet aggregation and platelet free calcium were measured after incubation of platelets with leptin alone (5-500 ng/ml), or leptin (50 and 100 ng/ml) in combination with anti-human leptin receptor long form antibody (anti-ObRb-Ab, 1:800-1:100 dilutions), PLC inhibitor U73122 (3.125-25 mM), PLA 2 inhibitor AACOCF3 (1.25-10 mM), or PKC inhibitor Ro31-8220 (1.25-10 mM). RESULTS: Platelet stimulation with leptin leads to a significant and dose-dependent increase in ADP-induced platelet aggregation and platelet free calcium concentrations. Leptin effects on both platelet aggregation and calcium mobilization were completely abated by the co-incubation with leptin and anti-ObRb-Ab. Leptin-induced platelet aggregation was dosedependently inhibited by U73122, AACOCF3, or Ro31-8220. The effect of leptin on intracellular calcium was inhibited in a dosedependent manner by incubation with U73122 and AACOCF3, but not with Ro31-8220. CONCLUSIONS: Our study confirms that leptin is able to enhance ADP-induced aggregation of human platelets, and raise the possibility that PLC, PKC, PLA 2 , and calcium could play a relevant role in mediating the proaggregating action of leptin.

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Effect of Leptin on Arterial Thrombosis Following Vascular Injury in Mice

Abstract: Leptin contributes to arterial thrombosis following vascular injury in vivo and these prothrombotic effects appear to be mediated through the platelet leptin receptor.

Cited by 220 publications

References 16 publications

Short-term very low-calorie diet in obese females improves the haemostatic balance through the reduction of leptin levels, PAI-1 concentrations and a diminished release of platelet and leukocyte-derived microparticles

Short-term very low-calorie diet in obese females improves the haemostatic balance through the reduction of leptin levels, PAI-1 concentrations and a diminished release of platelet and leukocyte-derived microparticles

Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients

Identifying pathways involved in leptin-dependent aggregation of human platelets

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