Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity.
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.
Konstantinides
S
S
Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Schäfer
K
K
Koschnick
S
S
Loskutoff
D J
DJ
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000473:pathology*; D001792:Blood Platelets / Q000187:drug effects; D020738:Leptin / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000503:physiopathology*; D010641:Phenotype; D010974:Platelet Aggregation / Q000502:physiology*; D013927:Thrombosis / Q000503:physiopathology*
D020738:Leptin; D000244:Adenosine Diphosphate