Resistance to acute NO-mimetic and EDHF-mimetic effects of leptin in the metabolic syndrome.
OBJECTIVE
We examined mechanisms leading to the impairment of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-dependent vasorelaxation in response to acutely administered leptin in rats with the metabolic syndrome.


METHODS
Effects of leptin on blood pressure and NO and cGMP in the aortic wall were studied in four groups of rats: (1) lean control, (2) obese, fed "cafeteria diet" for 3months (hyperleptinemia and hyperinsulinemia), (3) hyperleptinemia induced by administration of exogenous leptin for 8days, and (4) fructose-fed, receiving 20% fructose in the drinking water for 8weeks (hyperinsulinemia with slightly elevated leptin).


RESULTS
Stimulatory effect of leptin on NO and cGMP production in the aortic wall was impaired in obese and hyperleptinemic groups but not in the fructose group. In contrast, EDHF-mimetic effect of leptin was impaired in obese and fructose-fed but not in the hyperleptinemic group. Leptin increased tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in the aortic wall, and this effect was impaired in obese and fructose-fed animals. The EDHF-mimetic effect of leptin was abolished by phosphoinositide 3-kinase inhibitor, wortmannin, whereas its effect on NO was not. In addition, IRS-1 phosphorylation at Ser(307) and Ser(612) was enhanced in obese and fructose-fed but not in hyperleptinemic rats.


CONCLUSIONS
These results indicate that: (1) long-term hyperleptinemia induces resistance to acute vascular NO-mimetic effect of leptin in obesity/metabolic syndrome, (2) leptin stimulates EDHF in IRS-1 and PI3K-dependent manner, and this effect is impaired in obesity due to excessive serine phosphorylation of IRS-1.
Bełtowski
Jerzy
J
Department of Pathophysiology, Medical University, Lublin, Poland. jerzy.beltowski@am.lublin.pl
Wójcicka
Grazyna
G
Jamroz-Wiśniewska
Anna
A
Marciniak
Andrzej
A
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001685:Biological Factors / Q000378:metabolism* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D009765:Obesity / Q000097:blood / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D001685:Biological Factors; D007328:Insulin; D020738:Leptin; D011994:Recombinant Proteins; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D006152:Cyclic GMP