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Thromb Haemost 2008; 100(06): 1123-1129
DOI: 10.1160/TH08-05-0314
Platelets and Blood Cells
Schattauer GmbH

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

Claudia Dellas
1   Department of Cardiology and Pulmonology, Georg August University of Goettingen, Goettingen, Germany
,
Katrin Schäfer
1   Department of Cardiology and Pulmonology, Georg August University of Goettingen, Goettingen, Germany
,
Ilonka Rohm
1   Department of Cardiology and Pulmonology, Georg August University of Goettingen, Goettingen, Germany
,
Mareike Lankeit
1   Department of Cardiology and Pulmonology, Georg August University of Goettingen, Goettingen, Germany
,
Thomas Ellrott
2   Department of Nutritional Psychology, Georg August University of Goettingen, Goettingen, Germany
,
Vivien Faustin
2   Department of Nutritional Psychology, Georg August University of Goettingen, Goettingen, Germany
,
Joachim Riggert
3   Department of Transfusion Medicine, Georg August University of Goettingen, Goettingen, Germany
,
Gerd Hasenfuss
1   Department of Cardiology and Pulmonology, Georg August University of Goettingen, Goettingen, Germany
,
Stavros Konstantinides
1   Department of Cardiology and Pulmonology, Georg August University of Goettingen, Goettingen, Germany
› Author AffiliationsFinancial support: The study was supported by grants from the German Research Foundation (to C.D., K.S., and S.K.) and from the University of Goettingen (to C.D.).
Further Information

Publication History

Received: 20 May 2008

Accepted after minor revision: 24 September 2008

Publication Date:
23 November 2017 (online)

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Summary

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 µM) 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 ADPinduced platelet aggregation.

Keywords

Leptin - resistance - platelets - aggregation - obesity
 

  • References

  • 1 Caro JF, Sinha MK, Kolaczynski JW. et al. Leptin: the tale of an obesity gene. Diabetes 1996; 45: 1455-1462.
    CrossrefPubMedGoogle Scholar
  • 2 Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763-770.
    CrossrefPubMedGoogle Scholar
  • 3 Considine RV, Sinha MK, Heiman ML. et al. Serum immunoreactive-leptin concentrations in normalweight and obese humans. N Engl J Med 1996; 334: 292-295.
    CrossrefPubMedGoogle Scholar
  • 4 Munzberg H, Bjornholm M, Bates SH. et al. Leptin receptor action and mechanisms of leptin resistance. Cell Mol Life Sci 2005; 62: 642-652.
    CrossrefPubMedGoogle Scholar
  • 5 Huang W, Dedousis N, Bhatt BA. et al. Impaired activation of phosphatidylinositol 3-kinase by leptin is a novel mechanism of hepatic leptin resistance in diet-induced obesity. J Biol Chem 2004; 279: 21695-21700.
    CrossrefPubMedGoogle Scholar
  • 6 Rahmouni K, Morgan DA, Morgan GM. et al. Role of selective leptin resistance in diet-induced obesity hypertension. Diabetes 2005; 54: 2012-2018.
    CrossrefPubMedGoogle Scholar
  • 7 Wallace AM, McMahon AD, Packard CJ. et al. Plasma leptin and the risk of cardiovascular disease in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 2001; 104: 3052-3056.
    CrossrefPubMedGoogle Scholar
  • 8 Wolk R, Berger P, Lennon RJ. et al. Plasma leptin and prognosis in patients with established coronary atherosclerosis. J Am Coll Cardiol 2004; 44: 1819-1824.
    CrossrefPubMedGoogle Scholar
  • 9 Konstantinides S, Schäfer K, Koschnick S. et al. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108: 1533-1540.
    CrossrefPubMedGoogle Scholar
  • 10 Bodary PF, Westrick RJ, Wickenheiser KJ. et al. Effect of leptin on arterial thrombosis following vascular injury in mice. J Am Med Assoc 2002; 287: 1706-1709.
    CrossrefPubMedGoogle Scholar
  • 11 Corsonello A, Perticone F, Malara A. et al. Leptindependent platelet aggregation in healthy, overweight and obese subjects. Int J Obes Relat Metab Disord 2003; 27: 566-573.
    CrossrefPubMedGoogle Scholar
  • 12 Nakata M, Yada T, Soejima N. et al. Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes 1999; 48: 426-429.
    CrossrefPubMedGoogle Scholar
  • 13 Wallaschofski H, Kobsar A, Sokolova O. et al. Differences in platelet activation by prolactin and leptin. Horm Metab Res 2004; 36: 453-457.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Giandomenico G, Dellas C, Czekay RP. et al. The leptin receptor system of human platelets. J Thromb Haemost 2005; 03: 1042-1049.
    CrossrefPubMedGoogle Scholar
  • 15 Sugiyama C, Ishizawa M, Kajita K. et al. Platelet aggregation in obese and diabetic subjects: association with leptin level. Platelets 2007; 18: 128-134.
    CrossrefPubMedGoogle Scholar
  • 16 Elbatarny HS, Maurice DH. Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex. Am J Physiol Endocrinol Metab 2005; 289: E695-E702.
    CrossrefPubMedGoogle Scholar
  • 17 Corica F, Corsonello A, Lucchetti M. et al. Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients. Int J Obes (Lond) 2007; 31: 842-849.
    CrossrefPubMedGoogle Scholar
  • 18 Jancinova V, Nosal R, Petrikova M. Dose-response aggregometry--contribution to the precise platelet function evaluation. Thromb Res 1992; 65: 1-11.
    CrossrefPubMedGoogle Scholar
  • 19 Dellas C, Schafer K, Rohm IK. et al. Leptin signalling and leptin-mediated activation of human platelets: Importance of JAK2 and the phospholipases Cgamma2 and A(2). Thromb Haemost 2007; 98: 1063-1071.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Gomez-Ambrosi J, Salvador J, Silva C. et al. Increased cardiovascular risk markers in obesity are associated with body adiposity: role of leptin. Thromb Haemost 2006; 95: 991-996.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Bjorbaek C, El Haschimi K, Frantz JD. et al. The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem 1999; 274: 30059-30065.
    CrossrefPubMedGoogle Scholar
  • 22 Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A. et al. PTP1B regulates leptin signal transduction in vivo. Dev Cell 2002; 02: 489-495.
    CrossrefPubMedGoogle Scholar
  • 23 Juhan I, Gabrielli M, Jouve R. et al. [A study of platelet abnormalities in obese subjects (author’s transl)]. Diabete Metab 1980; 06: 17-24.
    PubMedGoogle Scholar
  • 24 Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000; 62: 413-437.
    CrossrefPubMedGoogle Scholar
  • 25 Bjorbaek C, Kahn BB. Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 2004; 59: 305-331.
    CrossrefPubMedGoogle Scholar
  • 26 Bates SH, Stearns WH, Dundon TA. et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 2003; 421: 856-859.
    CrossrefPubMedGoogle Scholar
  • 27 Elchebly M, Payette P, Michaliszyn E. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 1999; 283: 1544-1548.
    CrossrefPubMedGoogle Scholar
  • 28 Lam NT, Covey SD, Lewis JT. et al. Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver. J Mol Endocrinol 2006; 36: 163-174.
    CrossrefPubMedGoogle Scholar