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DOI: 10.1055/s-0028-1082037
© Georg Thieme Verlag KG Stuttgart · New York
Effects of Leptin Replacement on Risk Factors for Cardiovascular Disease in Genetically Leptin-deficient Subjects
Publication History
received 30.04.2008
accepted 28.05.2008
Publication Date:
22 August 2008 (online)
Introduction
Human obesity is associated with leptin resistance, elevated plasma leptin levels, and increased risk of arterial and venous thrombotic disease. Leptin excess may be not only a consequence of obesity [1], but may also have an etiopathogenic role on the proinflammatory and the prothrombotic states that are associated with adiposity [2] [3]. Those states, combined with insulin resistance, hypertension, and dyslipidemia, are part of the so-called metabolic syndrome (MetS). However, the ability for the different diagnostic criteria for MetS to predict cardiovascular disease (CVD) varies between populations [4] [5]. This makes the usefulness of the different diagnostic criteria for MetS, questionable. Therefore, many studies are trying to identify novel biomarkers that predict the risk for vascular diseases [6] [7].
It is suggested that leptin influences inflammation and coagulation through its effects on factors involved on platelet aggregability, thrombogenesis, and fibrinolysis. Due to these effects on coagulation, some studies have suggested that leptin could be considered as an independent risk factor for CVD [3] [8] [9]. However, other studies have presented conflicting results [10] [11] [12]. All studies have been carried out on humans with normal or high levels of leptin. Particularly in obese individuals, leptin resistance is frequently present [13], which may be a critical confounding factor for the analysis of the association between leptinemia and the risk for development of CVD. Therefore, a state in which there is complete absence of bioactive leptin is the best model to study the effects of leptin on biomarkers associated with increased risk for CVD, because in that case leptin resistance would not be increased.
We aimed to examine the effects of leptin on the factors associated with inflammation and coagulation in three leptin-deficient adults, while they were on recombinant methionyl human leptin (r-metHuLeptin) replacement treatment and after it was interrupted for research purposes in order to create a leptin-free state. To achieve that purpose, we measured the levels of an inflammatory biomarker (C-reactive protein), factors involved in the coagulation pathways (fibrinogen, prothrombin fragment F1+2, and coagulation factors II, VII, VIII, IX, X and XI), factors that are natural anticoagulants (protein C activity, total protein S activity, and antithrombin III), factors associated with platelet aggregability (von Willebrand factor antigen and ristocetin cofactor activity), factors that regulate fibrinolysis (tissue plasminogen activator and plasminogen activator inhibitor-1), and a marker of fibrinolysis (D-dimer) in these unique patients.