Obesity is associated with increased cardiovascular morbidity and mortality and with elevated circulating levels of the satiety factor leptin. This study provides evidence for a direct link between leptin and the risk for thrombotic complications in obese individuals. For example, although arterial injury provokes thrombosis in both lean and obese (ob/ob) mice, the time to complete thrombotic occlusion is significantly delayed in the ob/ob mice, and the thrombi formed are unstable and frequently embolize. The ob/ob mice lack leptin, and intraperitoneal administration of leptin to these mice before injury restores the phenotype of lean mice by shortening the time to occlusion, stabilizing the thrombi, and decreasing the patency rate. The thrombi that form when leptin receptor-deficient obese (db/db) mice are injured also are unstable. However, in this instance, leptin has no effect. Platelets express the leptin receptor, and leptin potentiates the aggregation of platelets from ob/ob but not db/db mice in response to known agonists. These results reveal a novel receptor-dependent effect of leptin on platelet function and hemostasis and provide new insights into the molecular basis of cardiovascular complications in obese individuals. The results suggest that these prothrombotic properties should be considered when developing therapeutic strategies based on leptin.
Stavros Konstantinides, Katrin Schäfer, Stefan Koschnick, David J. Loskutoff
Submitter: Andrea Corsonello | email@example.com
Department of Internal Medicine, University of Messina, Italy
Published February 12, 2002
Dear Sir, we have read with a great interest the paper by Konstantinides and coworkers (1). Their findings suggest that the prothrombotic effect of leptin may be involved in the pathophysiology of the excess risk of cardiovascular disease in obesity. We think that this is an interesting paper providing innovative and very important informations about the molecular basis of the association between obesity and cardiovascular comorbidity. Recently, we studied the effects of leptin on platelet aggregation in healthy humans, and we found that platelet aggregation was significantly enhanced by the pre-incubation with leptin at a concentration of 5-100 ng/ml. This effect was dose-dependent, and it was completely abated by the pre-incubation with leptin and anti-long form leptin receptor antibody (5- 10 microl) (2). Our results are in agreement with recent studies suggesting that leptin may promote platelet aggregation through the stimulation of the long form of leptin receptor on platelet membrane (1, 3). At variance, Ozata and coworkers showed that similar to findings in obese humans, homozygous or heterozygous leptin deficiency is associated with increased platelet aggregation compared with controls, and that higher concentrations of leptin do not increase platelet aggregation (4). It is difficult to explain the discrepancy between these findings, but it should be considered that the interactions between leptin and other established modulators of platelet function (e.g. insulin, catecholamines) in the regulation of platelet aggregation are still to be elucidated. Furthermore, the role of other intracellular second messengers (e.g. free calcium, phospholipase C) in mediating leptin effects on platelet aggregation is largely unknown, and we intend to study this concern in the future.
We think that this is a very exciting research field, and further studies are needed for at least two major reasons: first, to investigate the possibility that platelet might represent a site of leptin- resistence in human obesity; second, to establish if leptin administration for therapeutic purpose is associated to an excess risk of thrombotic events. References
1. Konstantinides S, Schafer K, Koschnick S, Loskutoff DJ. Leptin- dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108: 1533-1540
2. Corsonello A, Malara A, Ientile R, Corica F. Leptin enhances ADP- induced platelet aggregation in healthy subjects. Obes Res 2002 (in press).
3. Nakata M, Yada T, Soejima N, Maruyama I. Leptin promotes platelet aggregation of human platelets via the long form of its receptor. Diabetes 1999; 48: 426-429.
4. Ozata M, Avcu F, Durmus O, Yilmaz I, Ozdemir IC, Yalcin A. Leptin does not play a major role in platelet aggregation in obesity and leptin deficiency. Obes Res 2001; 9: 627-630.