Abstract 6256: Absence of Leptin Resistance in Platelets from Obese Individuals Suggests a Mechanism for Increased Thrombosis Risk in Obesity

Abstract

Clinical studies have demonstrated that elevated leptin levels, such as frequently found in obesity, are an independent cardiovascular risk factor. We and others have shown that leptin promotes platelet aggregation and thrombosis. However, little is known about the existence of platelet resistance to leptin, particularly in the setting of obesity and central leptin resistance. In the present study, we examined the effects of leptin on platelet aggregation in morbidly obese subjects (n=40; BMI 41.6±1.1 kg/m2; leptin 49.7±3.4 ng/mL) in comparison to normal-weight controls (n=36; BMI 23.3±0.4; leptin 6.5±0.7). The aggregatory response to ADP was significantly increased in platelets from obese donors compared to controls as shown by a left-shift in the ADP dose curves. Thus, percent platelet aggregation at 2, 3, 4, and 5 μM ADP was 18.7±4.8 in the obese vs. 4.7±2.0 in controls (P=0.01), 37.2±6.6 vs. 17.1±4.4 (P=0.01), 60.8±6.0 vs. 37.8±6.5 (P=0.01), and 80.2±6.5 vs. 44.5±8.8 (P=0.002), respectively. Plasma leptin levels, but not the body-mass-index, were significantly higher in subjects with stronger (above the median) platelet aggregation in response to ADP compared to those with weaker (below the median) aggregation (35.9±5.1 vs. 22.4±4.1 ng/mL; P=0.04). In further experiments, exogenous leptin stimulation promoted ADP-induced platelet aggregation by 25% on average, and there was no difference in the responsiveness to leptin between platelets from obese and those from lean donors (controls; P=0.99). Using Western blot analysis we found that leptin induced phosphorylation of the signaling molecules JAK2 and STAT3 to a similar extent in platelets from both groups. Expression of potential mediators of leptin resistance (SOCS3 and PTP1B) also did not differ in platelets from obese and control subjects. Taken together, our data indicate that platelets from obese donors show increased aggregatory response to ADP, which might partly result from the increased circulating leptin levels. Platelets from obese individuals were not resistant to the enhancing effects of leptin on ADP-induced aggregation. Our results thus support the existence of a direct link between obesity, hyperleptinemia and thrombosis.