Absence of leptin resistance in platelets from morbidly obese individuals may contribute to the increased thrombosis risk in obesity

Abstract

Clinical studies have shown that elevated leptin levels are an independent cardiovascular risk factor. However, little is known about the existence of platelet resistance to leptin in the setting of obesity. 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 kg/m2; leptin, 6.5 +/- 0.7 ng/ml). The aggregatory response to increasing concentrations of adenosine diphosphate (ADP) (2, 3, 4, and 5 microM) was significantly increased in platelets from obese compared to lean donors, reflecting a left shift in the dose-response curve. Plasma leptin levels, but not BMI, were significantly higher in subjects with stronger (above the median) compared to weaker (below the median) platelet aggregation at all ADP concentrations tested. In further experiments, stimulation (preincubation) with leptin (500 ng/ml) promoted ADP-induced platelet aggregation by approximately 25%, and there was no difference between platelets from obese and those from lean donors regarding the responsiveness to leptin (p = 0.99). Western blotting revealed that leptin induced phosphorylation of 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. In conclusion, our data indicate that platelets from obese donors show increased aggregatory response to ADP, and that this might partly be the consequence of increased circulating leptin levels. Platelets from obese donors are not resistant to the enhancing effects of leptin on ADP-induced platelet aggregation.

Mechanistic View of Risk Factors for Venous Thromboembolism

“…The predisposition of obese individuals to VTE is in part determined by increased ADP-induced platelet aggregation, which in turn may be determined by the increased leptin levels that are often found in obese individuals. 28 As mentioned above, platelet activation may also play a role in antiphospholipid syndrome.…”

“…The predisposition of obese individuals to VTE is in part determined by increased ADP-induced platelet aggregation, which in turn may be determined by the increased leptin levels that are often found in obese individuals. 28 As mentioned above, platelet activation may also play a role in antiphospholipid syndrome.Myeloproliferative diseases such as polycythemia vera and essential thrombocytosis lead to increases in platelet number and function and VTE occurs in a large proportion of patients. 29 It is likely that this risk increase is a direct consequence of the change in platelet number rather than the presence of the JAK2V617F mutation that is present in virtually all patients with polycythemia and in about half of those with essential thrombocytosis.…”

Elevated body fat is a risk factor for venous thromboembolism and thrombotic complications

“…In cases of obesity, leptin levels are elevated, so it creates a certain resistance to its action. Leptin has been associated with ADP-dependent platelet aggregation [17] and its levels correlate with levels of antigenic tPA (tissue plasminogen activator) [18]. Higher levels of tPA signify elevated concentrations of PAI-1.…”

Factors Associated with Early Platelet Activation in Obese Children

“…The involvement of leptin in increased platelet activation in human obesity is not universally accepted, since several studies [25][26][27] provided conflicting results about platelet responsiveness to leptin in overweight and obesity in adults. Like Fochini et al, 10 we confirm that obese children have higher leptin and platelet concentrations compared with nonobese children, so this increase could favor early functional alterations and represent higher risk for developing early atherosclerosis and CVD.…”