Complications of atherosclerosis are the leading cause of morbidity
and mortality in industrialized societies. Obesity has emerged as an independent
risk factor for complications of atherosclerotic vascular disease. Leptin,
a hormone produced by the adipocyte, increases with obesity and appears to
modulate energy balance and food intake. In addition, other actions of leptin
have been proposed, including an in vitro effect on platelet aggregation.
Thus, the elevated plasma leptin levels in obese individuals may promote vascular
To test the hypothesis that leptin contributes to in vivo thrombosis
via the leptin receptor.
Design and Materials
Between September 2000 and September 2001, a vascular thrombosis model
was used to test male 10- to 12-week-old mice completely deficient in leptin
or the leptin receptor and mice with platelet leptin-receptor deficiency.
Main Outcome Measure
Time to formation of an occlusive thrombus in the common carotid artery
following experimentally induced endothelial injury.
Following onset of vascular injury, wild-type mice (n = 8) formed occlusive
thrombosis in a mean (SD) of 42.2 (4.6) minutes, whereas leptin-deficient
(n = 5) and leptin receptor–deficient mice (n = 7) formed occlusive
thrombosis in 75.2 (10.1) and 68.6 (10.3) minutes, respectively (leptin deficient
vs wild-type mice, P = .008; leptin-receptor–deficient
vs wild-type, P = .03). When recombinant murine leptin
was administered to leptin-deficient mice (n = 4), the time to occlusion was
reduced to 41.8 (6.6) minutes (P = .035 vs vehicle
control). Following bone marrow transplantation from leptin receptor–deficient
(donor) mice to wild-type (recipient) mice, the time to occlusion was prolonged
from 22.3 (2.8) minutes in wild-type mice receiving wild-type marrow (n =
3) to 56.8 (5.0) minutes in wild-type mice receiving leptin receptor–deficient
bone marrow (n = 5) (P = .003).
Leptin contributes to arterial thrombosis following vascular injury
in vivo and these prothrombotic effects appear to be mediated through the
platelet leptin receptor.