LEPTIN INCREASES THROMBOXANE A2 FORMATION IN THE RAT
Andrzej Marciniak, Grażyna Wójcicka, and Jerzy Bełtowski (Poland)
Abstract
Chronic hyperleptinemia may contribute to various complications of obesity including atherosclerosis, however, the underlying mechanisms are incompletely clear. We examined the effect of leptin on platelet activity by measuring stable metabolites of thromboxane A2 (TXA2), TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2, in plasma and urine. In vitro, leptin stimulated TXB2 formation by platelet-rich plasma (PRP). In vivo, leptin (1 mg/kg ip.) increased urinary excretion of 11-dehydro-TXB2 and 2,3-dinor-TXB2. Urinary excretion of these metabolites was also elevated in rats made hyperleptinemic by administration of recombinant leptin (0.5 mg/kg/day) for 8 days. The stimulatory effect of leptin on TXB2 formation in PRP isolated from hyperleptinemic animals was impaired in comparison to the control group. In rats made obese, hyperleptinemic and hyperinsulinemic/insulin resistant by cafeteria diet administered for 3 months, acute stimulatory effect of leptin on TXB2 formation by PRP was not impaired. In rats made insulin resistant by fructose feeding for 8 weeks, stimulatory effect of leptin on TXB2 formation in PRP was augmented in comparison to the control group. Insulin sensitizer, rosiglitazone, decreased insulin level and attenuated the stimulatory effect of leptin on TXB2 formation in obese and fructose-fed animals. In contrast, rosiglitazone had no effect on insulin level or leptin-induced TXB2 formation in control rats and rats receiving recombinant leptin for 8 days. These results indicate that: (i) leptin stimulates platelet TXA2 formation both in vitro and in vivo, (ii) chronic hyperleptinemia impairs acute stimulatory effect of leptin on platelet activity if insulin sensitivity is normal, (iii) insulin resistance/hyperinsulinemia augments the stimulatory effect of leptin on TXA2 formation, which results in normal platelet sensitivity to leptin in obesity associated with both hyperleptinemia and hyperinsulinemia, and (iv) PPAR-γ agonists such as rosiglitazone decrease platelet sensitivity to leptin by reducing insulin resistance.
Adipobiology 2009; 1: 77-85
Key words: platelets, obesity, metabolic syndrome, atherosclerosis, rosiglitazone
Received 30 July 2009, accepted 25 August 2009.
Correspondence and reprint request: Dr Jerzy Bełtowski, Department of Pathophysiology, Medical University, ul. Jaczewskiego 8, PL-20-090 Lublin, Poland.
Tel: +48 81 7187365, Fax: +48 81 7187364,
E-mail: jerzy.beltowski@am.lublin.pl
