Tkivna Specifičnost Efekata 17ß-Estradiola na Signalni put Insulina

Abstract

Insulin i estradiol imaju va.nu ulogu u regulaciji metabolizma ugljenih hidrata i lipida. Razli.ita klini.ka istra.ivanja i eksperimentalni podaci ukazuju da varijacije u koncentraciji estrogena uti.u na insulinsko delovanje. Cilj ove studije je bilo pore.enje uticaja estradiola na po.etne molekule insulinskog signalnog puta u glavnim ciljnim tkivima za insulin (jetra) i estradiol (uterus), kao i u srcu, u kome oba hormona ostvaruju zna.ajne efekte. Ovarijektomisane .enke pacova su tretirane estradiolom 6 h pre analize sadr.aja proteina i iRNK molekula signalnog puta insulina. Da bi se istakli efekti estradiola na fosforilacije i asocijacije molekula relevantne za insulinski signalni put, .ivotinje su dodatno injecirane insulinom 30 min pre eksperimenta. Tretman estradiolom nije promenio nivo insulina i glukoze u plazmi, ali je doveo do zna.ajnog smanjenja nivoa slobodnih masnih kiselina i pove.anja te.ine uterusa. U jetri, tretman estradiolom je doveo do smanjenja fosforilacije IR, kao i smanjenja proteinskog sadr.aja IRS-1, .to navodi na zaklju.ak da je estradiol suprimirao efekte insulina preko IR/IRS-1 puta i verovatno ih usmerio na alternativni put, .to je potkrepljeno i pove.anjem proteinskog sadr.aja IRS-2. U uterusu je tretman estradiolom nakon 6 h doveo do statisti.ki zna.ajnog pove.anja proteinskog sadr.aja skoro svih ispitivanih molekula signalnog puta insulina. U srcu je estradiol uzrokovao pove.anje asocijacije IRS-1/p85, pove.anja sadr.aja proteina i iRNK p85, kao i pove.anje fosforilacije Akt na Ser⁴⁷³. S druge strane, tretman estradiolom je u srcu izazvao i smanjenje fosforilacije tirozina IR, smanjenje proteinskog sadr.aja IRS-2 i iRNK oba IRS proteina. Rezultati ove studije ukazuju na to da tretman estradiolom indukuje tkivno specifi.ne promene u insulinskom signalnom putu. Posledice tretmana estradiolom na molekule insulinskog signalnog puta su o.iglednije u uterusu, ali je njihov fiziolo.ki zna.aj za insulinsko delovanje verovatno ve.i u jetri. S druge strane, rezultati dobijeni u srcu sugeri.u veoma kompleksnu ulogu estradiola u fiziologiji srca, koja se manifestuje i kombinacijom pozitivnog i negativnog, genomskog i negenomskog delovanja ovog hormona na molekule signalnog puta insulina.

Alternate abstract:

Insulin and estradiol play important role in regulation of carbohydrate and lipid metabolism. Various clinical observations and experimental data suggest that variations in the concentration of estrogens affect insulin action. The aim of the present study was to compare the impact of estradiol on early steps of insulin signaling in main target tissues of insulin (the liver) and estradiol (the uterus), and in the heart, where both hormones realize important effects. Ovariectomized female rats were treated with estradiol 6 h prior to analysis of protein and mRNA content of insulin signaling molecules. To delineate estradiol effects on phosphorylations and molecular associations relevant for insulin signaling, animals were treated additionally with insulin 30 min before the experiment. Treatment with estradiol did not change the levels of plasma insulin and glucose, but it significantly decreased the free fatty acid level and increased uterine weight. In liver, estradiol treatment decreased IR phosphorylation and IRS-1 protein content, suggesting that estradiol suppressed insulin action through IR/IRS-1 and probably redirected it to alternative pathway. This conclusion is supported with increase of IRS-2 protein content. In uterus, estradiol treatment resulted in significant increase of protein content of almost all analyzed molecules. In heart, estradiol increased IRS-1/p85 association, p85 protein and mRNA level, and Ser⁴⁷³Akt phosphorylation. On the other hand, estradiol treatment decreased tyrosine phosphorylation of cardiac IR, protein content of IRS-2, and mRNA of both IRS proteins. These results suggest that estradiol treatment induces tissue-specific changes in insulin signaling. Consequences of estradiol treatment on insulin signaling molecules are more apparent in uterus, but their physiological relevance for insulin action is probably more important in liver. On the other hand, results obtained in heart suggest very complex role of estradiol in heart physiology, represented by, amongst other effects, combination of positive and negative, genomic and nongenomic actions of this hormone on insulin signaling molecules.